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Innate immune defense mechanisms against infection and cancer encompass the modulation of pattern recognition receptor (PRR)‐mediated inflammation, including upregulation of various transcription factors and the activation of pro‐inflammatory pathways important for immune surveillance. Dysfunction of PRRs‐mediated signaling has been implicated in cancer and autoimmune diseases, while the overactivation of PRRs‐driven responses during infection can lead to devastating consequences such as acute lung injury or sepsis. We used crystal structure‐based design to develop immunomodulatory lipopolysaccharide (LPS) mimetics targeting one of the ubiquitous PRRs, Toll‐like Receptor 4 (TLR4). Taking advantage of an exo‐anomeric conformation and specific molecular shape of synthetic nonreducing β,β‐diglucosamine, which was investigated by NMR, we developed two sets of lipid A mimicking glycolipids capable of either potently activating innate immune responses or inhibiting pro‐inflammatory signaling. Stereoselective 1,1′‐glycosylation towards fully orthogonally protected nonreducing GlcNβ(1↔1′)βGlcN followed by stepwise assembly of differently functionalised phosphorylated glycolipids provided biologically active molecules that were evaluated for their ability to trigger or to inhibit cellular innate immune responses. Two LPS mimetics, identified as potent TLR4‐specific inducers of the intracellular signaling pathways, serve as vaccine adjuvant‐ and immunotherapy candidates, while anionic glycolipids with TLR4‐inhibitory potential hold therapeutic promise for the management of acute or chronic inflammation. [ABSTRACT FROM AUTHOR]

Viral infections pose significant threats to human health, leading to a diverse spectrum of infectious diseases. The innate immune system serves as the primary barrier against viruses and bacteria in the early stages of infection. A rapid and forceful antiviral innate immune response is triggered by distinguishing between self-nucleic acids and viral nucleic acids. RNA-binding proteins (RBPs) are a diverse group of proteins which contain specific structural motifs or domains for binding RNA molecules. In the last decade, numerous of studies have outlined that RBPs influence viral replication via diverse mechanisms, directly recognizing viral nucleic acids and modulating the activity of pattern recognition receptors (PRRs). In this review, we summarize the functions of RBPs in regulation of host-virus interplay by controlling the activation of PRRs, such as RIG-I, MDA5, cGAS and TLR3. RBPs are instrumental in facilitating the identification of viral RNA or DNA, as well as viral structural proteins within the cellular cytoplasm and nucleus, functioning as co-receptor elements. On the other hand, RBPs are capable of orchestrating the activation of PRRs and facilitating the transmission of antiviral signals to downstream adaptor proteins by post-translational modifications or aggregation. Gaining a deeper comprehension of the interaction between the host and viruses is crucial for the development of novel therapeutics targeting viral infections. [ABSTRACT FROM AUTHOR]

Breast cancer stands as a primary malignancy among women, ranking second in global cancer-related deaths. Despite treatment advancements, many patients progress to metastatic stages, posing a significant therapeutic challenge. Current therapies primarily target cancer cells, overlooking their intricate interactions with the tumor microenvironment (TME) that fuel progression and treatment resistance. Dysregulated innate immunity in breast cancer triggers chronic inflammation, fostering cancer development and therapy resistance. Innate immune pattern recognition receptors (PRRs) have emerged as crucial regulators of the immune response as well as of several immune-mediated or cancer cell-intrinsic mechanisms that either inhibit or promote tumor progression. In particular, several studies showed that the Toll-like receptor 2 (TLR2) and the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathways play a central role in breast cancer progression. In this review, we present a comprehensive overview of the role of TLR2 and STING in breast cancer, and we explore the potential to target these PRRs for drug development. This information will significantly impact the scientific discussion on the use of PRR agonists or inhibitors in cancer therapy, opening up new and promising avenues for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Crustacean species are among the most valued seafood with socioeconomic and ecological implications in the global fisheries sector. Microbial infections to the farming stock due to continued expansion and aquaculture puts global crustacean production at risk. Understanding and reviewing the complex innate immune system of crustaceans would be pivotal in formulating informed decisions for the control and management of epidemic diseases, thus making the global crustacean aquaculture industry sustainable. Under the purview of innate immunity in crustaceans, pattern recognition receptors (PRRs) represent the sensors capable of discriminating non‐self pathogenic modules and invoking the activation of immune responses. The immunity to infections can be manifested at cellular (via phagocytosis, apoptosis, nodulation and encapsulation) and humoral (effected by prophenoloxidase cascade, lectins, antimicrobial proteins) levels leading to the elimination of pathogens or subversion of the pathogenic implications. In this review, we discuss the participatory role of 12 types of PRRs identified from crustacean species with an exhaustive focus on structural and functional specificities in binding to pathogens and possible execution of the immune activity. Moreover, we have elaborated on the PRRs‐associated or possible signalling cascades (Toll‐NFκB, IMD‐NFκB and JAK‐STAT) in crustacean species that could bridge our understanding of the resistance or susceptibility of the host to varied pathogenic infections thus providing clues to the regulatory mechanisms involved in pathogenesis of infectious diseases and mechanisms of immunity. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cause of cancer worldwide and is the leading cause of mortality for women across most of the world. Immunotherapy is a burgeoning area of cancer treatment, including for breast cancer; these are therapies that harness the power of the immune system to clear cancerous cells. Toll-like receptor 3 (TLR3) is an RNA receptor found in the endosome, and ligands that bind to TLR3 are currently being tested for their efficacy as breast cancer immunotherapeutics. The current review introduces TLR3 and the role of this receptor in breast cancer, and summarizes data on the potential use of TLR3 ligands, mainly polyinosinic:polycytidylic acid and its derivatives, as breast cancer monot [ABSTRACT FROM AUTHOR]

Innate immune receptors that form complexes with secondary receptors, activating multiple signalling pathways, modulate cellular activation and play essential roles in regulating homeostasis and immunity. We have previously identified a variety of bovine C-type lectin-like receptors that possess similar functionality than their human orthologues. Mincle (CLEC4E), a heavily glycosylated monomer, is involved in the recognition of the mycobacterial component Cord factor (trehalose 6,6′-dimycolate). Here we characterise the bovine homologue of Mincle (boMincle), and demonstrate that the receptor is structurally and functionally similar to the human orthologue (huMincle), although there are some notable differences. In the absence of cross-reacting antibodies, boMincle-specific antibodies were created and used to demonstrate that, like the human receptor, boMincle is predominantly expressed by myeloid cells. BoMincle surface expression increases during the maturation of monocytes to macrophages. However, boMincle mRNA transcripts were also detected in granulocytes, B cells, and T cells. Finally, we show that boMincle binds to isolated bovine CD4+ T cells in a specific manner, indicating the potential to recognise endogenous ligands. This suggests that the receptor might also play a role in homeostasis in cattle. [ABSTRACT FROM AUTHOR]

Filoviruses are a group of single-stranded negative sense RNA viruses. The most well-known filoviruses that affect humans are ebolaviruses and marburgviruses. During infection, they can cause life-threatening symptoms such as inflammation, tissue damage, and hemorrhagic fever, with case fatality rates as high as 90%. The innate immune system is the first line of defense against pathogenic insults such as filoviruses. Pattern recognition receptors (PRRs), including toll-like receptors, retinoic acid-inducible gene-I-like receptors, C-type lectin receptors, AIM2-like receptors, and NOD-like receptors, detect pathogens and activate downstream signaling to induce the production of proinflammatory cytokines and interferons, alert the surrounding cells to the threat, and clear infected and damaged cells through innate immune cell death. However, filoviruses can modulate the host inflammatory response and innate immune cell death, causing an aberrant immune reaction. Here, we discuss how the innate immune system senses invading filoviruses and how these deadly pathogens interfere with the immune response. Furthermore, we highlight the experimental difficulties of studying filoviruses as well as the current state of filovirus-targeting therapeutics. [ABSTRACT FROM AUTHOR]

The Asian seabass, Lates calcarifer , is a key species in Asian aquaculture due to its nutritional value and adaptability. However, disease outbreaks, particularly viral and bacterial infections, pose significant challenges to its production. Immunostimulants offer promising solutions but raise safety concerns. Paraprobiotics and postbiotics (CPP) emerge as safer alternatives, exerting health benefits without live microorganisms. This study investigated the potential of probiotic paraprobiotic and postbiotic supplements derived from Bacillus subtilis to enhance the immune response and antioxidant capacity of Asian seabass and improve their resistance to Streptococcus iniae infection. Analysis of antioxidant activity and lipid peroxidation revealed significant improvements in fish supplemented with CPP, indicating their effectiveness in mitigating oxidative stress. Immunological assays demonstrated enhanced growth performance and serum immunity, including increased alternative complement activity, immunoglobulin levels, and phagocytic activity, in supplemented fish. Furthermore, upregulated expression of proinflammatory cytokines (TNF-α, IL-6, IL-1β) and pattern recognition receptors (NLRC3, TLR22, MDA5) in immune tissues. Fish supplemented with CPP exhibited higher resistance and survival rates against S. iniae infection challenge compared to control groups. The study elucidates the mechanisms underlying the immunomodulatory effects of CPP, shedding light on their potential applications in aquaculture. • Paraprobiotics and postbiotics (CPP) enhance fish immunity by modulating pattern recognition receptor (PPRs). • Feeding Asian seabass with CCP supplements improved growth and immune responses. • CPP improve fish health by modulating antioxidant systems. • CCP could enhance fish resistance and survival rates against S. iniae infection. [ABSTRACT FROM AUTHOR]

Innate immunity is a primary defense system against microbial infections. Innate immune pattern recognition receptors (PRRs) play pivotal roles in detection of invading pathogens. When pathogens, such as bacteria and viruses, invade our bodies, their components are recognized by PRRs as pathogen-associated molecular patterns (PAMPs), activating the innate immune system. Cellular components such as DNA and RNA, acting as damage-associated molecular patterns (DAMPs), also activate innate immunity through PRRs under certain conditions. Activation of PRRs triggers inflammatory responses, interferon-mediated antiviral responses, and the activation of acquired immunity. Research on innate immune receptors is progressing rapidly. A variety of these receptors has been identified, and their regulatory mechanisms have been elucidated. Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) constitute a major family of intracellular PRRs and are involved in not only combating pathogen invasion but also maintaining normal homeostasis. Some NLRs are known to form multi-protein complexes called inflammasomes, a process that ultimately leads to the production of inflammatory cytokines and induces pyroptosis through the proteolytic cascade. The aberrant activation of NLRs has been found to be associated with autoimmune diseases. Therefore, NLRs are considered targets for drug discovery, such as for antiviral drugs, immunostimulants, antiallergic drugs, and autoimmune disease drugs. This review summarizes our recent understanding of the activation and regulation mechanisms of NLRs, with a particular focus on their structural biology. These include NOD2, neuronal apoptosis inhibitory protein (NAIP)/NLRC4, NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLRP6, and NLRP9. NLRs are involved in a variety of diseases, and their detailed activation mechanisms based on structural biology can aid in developing therapeutic agents in the future. [ABSTRACT FROM AUTHOR]

C-type lectins (CTLs) are glycan-binding pattern recognition receptors (PRRs) that can bind to carbohydrates on pathogen surfaces, triggering immune responses in shrimp innate immunity. In this study, a unique Ca2+-inhibited CTL named Fc Lec was identified and characterized in Chinese shrimp Fenneropenaeus chinensis. The full-length cDNA sequence of Fc Lec was 976 bp (GenBank accession number KU361826), with a 615 bp open reading frame (ORF) encoding 204 amino acids. Fc Lec possesses a C-type lectin-like domain (CTLD) containing four conserved cysteines (Cys105, Cys174, Cys192, and Cys200) and two sugar-binding site structures (QPD and LNP). The tertiary structure of Fc Lec deduced revealed three α-helices and eight β-pleated sheets. The mRNA expression levels of Fc Lec in hemocytes and the hepatopancreas were markedly elevated after stimulation with Vibrio anguillarum and white spot syndrome virus (WSSV). The recombinant Fc Lec protein exhibited Ca2+-independent hemagglutination and bacterial agglutination, but these activities were observed only in the presence of EDTA to chelate metal ions. These findings suggest that Fc Lec plays important and functionally distinct roles in the shrimp's innate immune response to bacteria and viruses, enriching the current understanding of the relationship between CTL activity and Ca2+ in invertebrates. [Display omitted] • A novel CTL, Fc Lec, were identified from F. chinensis. • Fc Lec plays distinct and significant roles in the innate immune system's reaction to microbial assaults. • Fc Lec exhibits Ca2+-independent and even Ca2+-inhibited activity. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors Mincle and NOD2 have been implicated in mycobacterial immunity. However, knockout (KO) animal infection studies with Mycobacterium tuberculosis (Mtb) have had mild/delayed phenotypes. Given that genetic susceptibility to infectious diseases can be polygenic, we hypothesized that murine double knockout (DKO) of Mincle and Nod2 would result in exacerbation of altered immunity to mycobacterial infection leading to a more extreme phenotype than either KO alone. To test this hypothesis, we monitored bacterial burden, immune responses and survival following in vivo infections with Mtb in DKO mice for comparison to wildtype (WT) and single KOs. Bacterial burden and immune responses were not significantly affected at 3 and 6 weeks after infection in all mutant mice. At later timepoints, Nod2 -KO mice had reduced survival compared to wildtype mice, and Mincle -KO survival was intermediate. Unexpectedly, dual disruption had no further effect; rather, DKO mice phenocopied Nod2 -KO mice. We observed that Mtb -related death, exclusively in mice with disrupted Nod2 , was accompanied by greater pulmonary cell death and distinct large necrotic foci. Therefore, determining how these receptors contribute to mycobacterial resistance will require analysis of immunophenotypes and their consequences on host pathology. [ABSTRACT FROM AUTHOR]

Inflammasomes are important multiprotein regulatory complexes of innate immunity and have recently emerged as playing divergent roles in numerous inflammation-associated cancers. Among these include gastric cancer (GC), the third leading cause of cancer-associated death worldwide, and we have previously discovered a pro-tumorigenic role for the key inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) in the spontaneous genetic gp130 F/F mouse model for GC. However, the identity of the specific pattern recognition receptors (PRRs) that activate tumor-promoting inflammasomes during GC is unknown. Here, we investigated the role of the best-characterized inflammasome-associated PRR, nucleotide-binding domain, and leucine-rich repeat containing receptor, pyrin domain-containing (NLRP) 3, in GC. In gastric tumors of gp130 F/F mice, although NLRP3 expression was elevated at the mRNA (qPCR) and protein (immunohistochemistry) levels, genetic ablation of NLRP3 in gp130 F/F: Nlrp3 -/- mice did not alleviate the development of gastric tumors. Similarly, cellular processes associated with tumorigenesis in the gastric mucosa, namely, proliferation, apoptosis, and inflammation, were comparable between gp130 F/F and gp130 F/F: Nlrp3 -/- mice. Furthermore, inflammasome activation levels, determined by immunoblotting and immunohistochemistry for cleaved Caspase-1, which along with ASC is another integral component of inflammasome complexes, were unchanged in gp130 F/F and gp130 F/F: Nlrp3 -/- gastric tumors. We also observed variable NLRP3 expression levels (mRNA and protein) among independent GC patient cohorts, and NLRP3 was not prognostic for survival outcomes. Taken together, these data suggest that NLRP3 does not play a major role in promoting inflammasome-driven gastric tumorigenesis, and thus pave the way for further investigations to uncover the key inflammasome-associated PRR implicated in GC. [ABSTRACT FROM AUTHOR]

The family of fibrinogen-related proteins (FREPs) is a group of proteins with fibrinogen-like (FBG) domains, which play important roles as pattern recognition receptors (PRRs) in the innate immune responses. In the present study, a fibrinogen-like protein was identified from the oyster Crassostrea gigas (defined as Cg FREP1). The open reading frame of Cg FREP1 was of 966 bp that encoded a predicted polypeptide of 321 amino acids comprising a signal peptide and a fibrinogen-like domain. The mRNA expression of Cg FREP1 was detected in all the examined tissues. The recombinant Cg FREP1 (r Cg FREP1) displayed binding activities to lipopolysaccharide (LPS), mannose (MAN), as well as Gram-positive bacteria (Micrococcus luteus and Staphylococcus aureus) and Gram-negative bacteria (Vibrio splendidus and Escherichia coli). The r Cg FREP1 displayed the agglutinating activity towards M. luteus , V. splendidus and E. coli in the presence of Ca2+. r Cg FREP1 was able to enhance the phagocytic activity of haemocytes towards V. splendidus , and exhibited binding activity to the CUB domain of Cg MASPL-1. These results suggest that Cg FREP1 not only serves as a PRR to recognize and agglutinate different bacteria but also mediates the haemocytes phagocytosis towards V. splendidus. • The mRNA expression of Cg FREP1 was able to be detected in all the examined tissues. • The Cg FREP1 displayed the binding activity to different PAMPs and bacteria. • Cg FREP1 was able to interact with the CUB domain of Cg MASPL-1. • The phagocytic activity of haemocytes was enhanced after V. splendidus incubated with Cg FREP1. [ABSTRACT FROM AUTHOR]

Cytosolic DNA receptor cyclic GMP‐AMP (cGAMP) synthase (cGAS) has been shown to be critically involved in the detection of cytosolic, self‐ and non‐self‐DNA, initiating a type I IFN response through the adaptor protein Stimulator of Interferon Genes (STING) and interferon regulatory factor 3 (IRF3). Current studies propose that canonical binding of dsDNA by cGAS depends on DNA length, but not on base sequence. In contrast, activation of TLR9 is sequence dependent. It requires unmethylated CpG dinucleotides in microbial DNA, which is mimicked by synthetic oligodeoxynucleotides (ODN). Here, we provide evidence that d‐type ODN (D‐ODN), but not K‐type ODN (K‐ODN), bind to human cGAS and activate downstream signaling. Transfection of D‐ODN into a TLR9‐deficient, human monocytic cell line (THP‐1) induced phosphorylation of IRF3 and secretion of IFN. This response was absent in cells with CRISPR/Cas9‐mediated cGAS‐ or STING‐deficiency. Utilizing a protein pulldown approach, we further demonstrate direct binding of D‐ODN to cGAS. Induction of a type I IFN response by D‐ODN was confirmed in human primary monocytes and monocyte‐derived macrophages. These results are relevant to our understanding of self–nonself‐discrimination by cGAS and to the pharmacologic effects of ODN, which currently are investigated in clinical studies. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) are evolutionarily ancient and crucial components of innate immunity, recognizing danger-associated molecular patterns (DAMPs) and activating host defenses. Basal non-bilaterian animals such as cnidarians must rely solely on innate immunity to defend themselves from pathogens. By investigating cnidarian PRR repertoires we can gain insight into the evolution of innate immunity in these basal animals. Here we utilize the increasing amount of available genomic resources within Cnidaria to survey the PRR repertoires and downstream immune pathway completeness within 15 cnidarian species spanning two major cnidarian clades, Anthozoa and Medusozoa. Overall, we find that anthozoans possess prototypical PRRs, while medusozoans appear to lack these immune proteins. Additionally, anthozoans consistently had higher numbers of PRRs across all four classes relative to medusozoans, a trend largely driven by expansions in NOD-like receptors and C-type lectins. Symbiotic, sessile, and colonial cnidarians also have expanded PRR repertoires relative to their non-symbiotic, mobile, and solitary counterparts. Interestingly, cnidarians seem to lack key components of mammalian innate immune pathways, though similar to PRR numbers, anthozoans possess more complete immune pathways than medusozoans. Together, our data indicate that anthozoans have greater immune specificity than medusozoans, which we hypothesize to be due to life history traits common within Anthozoa. Overall, this investigation reveals important insights into the evolution of innate immune proteins within these basal animals. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a progressive symmetric inflammation of the joints resulting in bone erosion and cartilage destruction with a progressive loss of function and joint deformity. An increased number of findings support the role of innate immunity in RA: many innate immune mechanisms are responsible for producing several cytokines and chemokines involved in RA pathogenesis, such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6, and IL-1. Pattern recognition receptors (PRRs) play a crucial role in modulating the activity of the innate arm of the immune response. We focused our attention over the years on the expression and functions of a specific class of PRR, namely formyl peptide receptors (FPRs), which exert a key function in both sustaining and resolving the inflammatory response, depending on the context and/or the agonist. We performed a broad review of the data available in the literature on the role of FPRs and their ligands in RA. Furthermore, we queried a publicly available database collecting data from 90 RA patients with different clinic features to evaluate the possible association between FPRs and clinic-pathologic parameters of RA patients. [ABSTRACT FROM AUTHOR]

Numerous cardiovascular disorders have atherosclerosis as their pathological underpinning. Numerous studies have demonstrated that, with the aid of pattern recognition receptors, cytokines, and immunoglobulins, innate immunity, represented by monocytes/macrophages, and adaptive immunity, primarily T/B cells, play a critical role in controlling inflammation and abnormal lipid metabolism in atherosclerosis. Additionally, the finding of numerous complement components in atherosclerotic plaques suggests yet again how heavily the immune system controls atherosclerosis. Therefore, it is essential to have a thorough grasp of how the immune system contributes to atherosclerosis. The specific molecular mechanisms involved in the activation of immune cells and immune molecules in atherosclerosis, the controversy surrounding some immune cells in atherosclerosis, and the limitations of extrapolating from relevant animal models to humans were all carefully reviewed in this review from the three perspectives of innate immunity, adaptive immunity, and complement system. This could provide fresh possibilities for atherosclerosis research and treatment in the future. [ABSTRACT FROM AUTHOR]

In the setting of myocardial infarction (MI), ischemia reperfusion injury (IRI) occurs due to occlusion (ischemia) and subsequent re-establishment of blood flow (reperfusion) of a coronary artery. A similar phenomenon is observed in heart transplantation (HTx) when, after cold storage, the donor heart is connected to the recipient's circulation. Although reperfusion is essential for the survival of cardiomyocytes, it paradoxically leads to additional myocardial damage in experimental MI and HTx models. Damage (or danger)-associated molecular patterns (DAMPs) are endogenous molecules released after cellular damage or stress such as myocardial IRI. DAMPs activate pattern recognition receptors (PRRs), and set in motion a complex signaling cascade resulting in the release of cytokines and a profound inflammatory reaction. This inflammatory response is thought to function as a double-edged sword. Although it enables removal of cell debris and promotes wound healing, DAMP mediated signalling can also exacerbate the inflammatory state in a disproportional matter, thereby leading to additional tissue damage. Upon MI, this leads to expansion of the infarcted area and deterioration of cardiac function in preclinical models. Eventually this culminates in adverse myocardial remodeling; a process that leads to increased myocardial fibrosis, gradual further loss of cardiomyocytes, left ventricular dilation and heart failure. Upon HTx, DAMPs aggravate ischemic damage, which results in more pronounced reperfusion injury that impacts cardiac function and increases the occurrence of primary graft dysfunction and graft rejection via cytokine release, cardiac edema, enhanced myocardial/endothelial damage and allograft fibrosis. Therapies targeting DAMPs or PRRs have predominantly been investigated in experimental models and are potentially cardioprotective. To date, however, none of these interventions have reached the clinical arena. In this review we summarize the current evidence of involvement of DAMPs and PRRs in the inflammatory response after MI and HTx. Furthermore, we will discuss various current therapeutic approaches targeting this complex interplay and provide possible reasons why clinical translation still fails. [ABSTRACT FROM AUTHOR]

Metabolic diseases pose a tremendous health threat in both developed and developing countries. The pathophysiology of metabolic diseases is complex but has been shown to be closely associated with sterile inflammation, which is initiated by various danger molecules derived from metabolic overload, such as oxidized low-density lipoproteins (OxLDLs), free fatty acids (FFAs), glucose, advanced glycation end products (AGEs), and cholesterol. These danger signals are sensed by pattern recognition receptors (PRRs) to activate proinflammatory signaling pathways and promote the release of proinflammatory mediators, leading to chronic low-grade inflammation. Although these harmful metabolic stimuli are generally regarded as damage-associated molecular patterns (DAMPs), a more specific definition and accurate classification for these DAMPs is still missing. In this opinion, we classify the harmful metabolic stimuli that can incite inflammatory responses and tissue damage via instigating PRRs as metabolism-associated molecular patterns (MAMPs), and we summarize their roles in metaflammation-mediated metabolic diseases. The pathogenesis and development of metabolic diseases are largely affected by metabolic inflammation, or 'metaflammation,' which is induced by metabolism-related danger signal molecules derived from metabolic overload. We define molecules derived from excess nutrients and their metabolites, capable of inciting inflammation via activating pattern recognition receptors (PRRs), as metabolism-associated molecular patterns (MAMPs), which are a subset of damage-associated molecular pattern (DAMPs) awaiting specific classification. MAMPs interact with PRRs to incite proinflammatory signaling pathways, such as NF-κB, MAPKs, and NLRP3 inflammasome pathways, driving the production of proinflammatory mediators and contributing to the initiation and progression of metabolic diseases. Targeting MAMPs and their downstream signaling molecules might be a promising strategy for developing therapeutic approaches to metabolic diseases. [ABSTRACT FROM AUTHOR]

Platelets are chief cells in hemostasis. Apart from their hemostatic roles, platelets are major inflammatory effector cells that can influence both innate and adaptive immune responses. Activated platelets have thromboinflammatory functions linking hemostatic and immune responses in several physiological and pathological conditions. Among many ways in which platelets exert these functions, platelet expression of pattern recognition receptors (PRRs), including TLR, Nod‐like receptor, and C‐type lectin receptor families, plays major roles in sensing and responding to pathogen‐associated or damage‐associated molecular patterns (PAMPs and DAMPs, respectively). In this review, an increasing body of evidence is compiled showing the participation of platelet innate immune receptors, including PRRs, in infectious diseases, sterile inflammation, and cancer. How platelet recognition of endogenous DAMPs participates in sterile inflammatory diseases and thrombosis is discussed. In addition, platelet recognition of both PAMPs and DAMPs initiates platelet‐mediated inflammation and vascular thrombosis in infectious diseases, including viral, bacterial, and parasite infections. The study also focuses on the involvement of innate immune receptors in platelet activation during cancer, and their contribution to tumor microenvironment development and metastasis. Finally, how innate immune receptors participate in platelet communication with leukocytes, modulating leukocyte‐mediated inflammation and immune functions, is highlighted. These cell communication processes, including platelet‐induced release of neutrophil extracellular traps, platelet Ag presentation to T‐cells and platelet modulation of monocyte cytokine secretion are discussed in the context of infectious and sterile diseases of major concern in human health, including cardiovascular diseases, dengue, HIV infection, sepsis, and cancer. [ABSTRACT FROM AUTHOR]

Maternal factors and exposure to pathogens have an impact on infant health. For instance, HIV exposed but uninfected infants have higher morbidity and mortality than HIV unexposed infants. Innate responses are the first line of defense and orchestrate the subsequent adaptive immune response and are especially relevant in newborns. To determine the association of maternal HIV infection with maternal and newborn innate immunity we analyzed the cytokine responses upon pattern recognition receptor (PRR) stimulations in the triad of maternal peripheral and placental blood as well as in cord blood in a cohort of mother-infant pairs from southern Mozambique. A total of 48 women (35 HIV-uninfected and 13 HIV-infected) were included. Women and infant innate responses positively correlated with each other. Age, gravidity and sex of the fetus had some associations with spontaneous production of cytokines in the maternal peripheral blood. HIV-infected women not receiving antiretroviral therapy (ART) before pregnancy showed decreased IL-8 and IL-6 PRR responses in peripheral blood compared to those HIV-uninfected, and PRR hyporesponsiveness for IL-8 was also found in the corresponding infant's cord blood. HIV infection had a greater impact on placental blood responses, with significantly increased pro-inflammatory, T H 1 and T H 17 PRR responses in HIV-infected women not receiving ART before pregnancy compared to HIV-uninfected women. In conclusion, innate response of the mother and her newborn was altered by HIV infection in the women who did not receive ART before pregnancy. As these responses could be related to birth outcomes, targeted innate immune modulation could improve maternal and newborn health. [ABSTRACT FROM AUTHOR]

Urinary tract infections are a severe public health problem. The emergence and spread of antimicrobial resistance among uropathogens threaten to further compromise the quality of life and health of people who develop acute and recurrent upper and lower urinary tract infections. The host defense mechanisms that prevent invasive bacterial infection are not entirely delineated. However, recent evidence suggests that versatile innate immune defenses play a key role in shielding the urinary tract from invading uropathogens. Over the last decade, considerable advances have been made in defining the innate mechanisms that maintain immune homeostasis in the kidney and urinary tract. When these innate defenses are compromised or dysregulated, pathogen susceptibility increases. The objective of this review is to provide an overview of how basic science discoveries are elucidating essential innate host defenses in the kidney and urinary tract. In doing so, we highlight how these findings may ultimately translate into the clinic as new biomarkers or therapies for urinary tract infection. [ABSTRACT FROM AUTHOR]

Introduction: Periodontal disease, infectious in origin and inflammatory in progression ultimately leads to destruction of periodontium. Pattern recognition receptors (PRRs) help in identifying the molecular patterns displayed on the bacteria and mount an immune response. Nucleotide-binding and oligomerization domain receptors (NOD1 and NOD2) are cytosolic PRRs involved in the immunopathogenic process involved in the periodontal diseases. This study was undertaken to evaluate distribution of NOD1 and NOD2 and to compare and correlate the NOD1 and NOD2 expression in gingival samples from healthy, chronic, and aggressive periodontitis participants. Materials and Methods: Sixty participants participated in the study and were divided into three groups of 20 individuals each - Group I (healthy), Group II (chronic periodontitis), and Group III (aggressive periodontitis) based on the inclusion and exclusion criteria. Gingival tissue samples were collected during periodontal flap surgery, crown lengthening procedure in periodontitis individuals and healthy controls, respectively. The levels of NOD1 and NOD2 in the gingival samples were analyzed using immunohistochemistry. Results: The NOD1 and NOD2 levels were higher in Group III (aggressive periodontitis) followed by Group II (chronic periodontitis) and lowest in Group I (healthy). Comparison of mean NOD1 and NOD2 between the three Groups showed statistically significant difference (P < 0.001). Positive correlation was observed on correlating NOD1 and NOD2 with the clinical parameters (gingival index, probing pocket depth, and clinical attachment loss). Conclusion: Epithelial localization of NOD1 and NOD2 was more in periodontitis than in healthy tissue. These findings indicate that NOD1 and NOD2 play an indispensable role at the forefront in innate immunity. [ABSTRACT FROM AUTHOR]

Purpose: Pathogens consist of a wide variety of evolutionarily conserved molecular structures that are recognized by pattern recognition receptors (PRRs) of innate immunity. Reasonably assuming that no single PRR is ever likely to be the sole trigger of the immune response during infection, a great deal remains unknown about collaborative mechanisms and consequential crosstalk effects between multiple PRRs belonging to different families. Here, we aimed to investigate inflammatory response to combined stimulation of cytosolic nucleotide-binding oligomerization domain (NOD) receptors: NOD1, NOD2 and membrane-bound C-type lectin receptors (CLRs): Mincle and Dectin-1 in comparison to individual stimulation both in vitro and in vivo. Materials and Methods: For in vitro studies, we used human monocytic THP-1 cells endogenously expressing NOD1,2, as well as Mincle and Dectin-1 receptors. Using reporter gene and immunoassay approaches, we measured activity of key proinflammatory transcription factors (NF-κB and AP-1) and cytokine production after addition of specific PRR agonists or their pairwise combinations. In vivo NF-κB activity (bioluminescent detection in NF-κB-Luc transgenic mice), as well as cytokine levels in mouse blood serum, was measured 3 hours after intramuscular injection of PRR agonists. Results: We detected that combined stimulation of NOD1/2 and C-type lectin receptors (Dectin-1, Mincle) strongly potentiates NF-κB and AP-1 transcription factor activity in human monocytic THP-1 cells, as well as resulting in enhanced levels of IL-8 cytokine production. We demonstrated that RIP2- and Syk-dependent signaling pathways downstream of NOD1/2 and Dectin-1/Mincle, respectively, are essential for the potentiated proinflammatory cell response. Lastly, we confirmed that synergy between NOD and C-type lectin receptors resulting in potentiated levels of NF-κB activation and cytokine (IL-6, KC) production also occurs in vivo. Conclusion: These findings originally indicate cooperation between NODs and CLRs, leading to potentiated levels of proinflammatory immune response both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Multicellular organisms live in close association with a plethora of microorganism, which have a profound effect on multiple host functions. As such, the microbiota and its host form an intimate functional entity, termed the metaorganism or holobiont. But how does the metaorganism communicate? Which receptors recognize microbial signals, mediate the effect of the microbiota on host physiology or regulate microbiota composition and homeostasis? In this review we provide an overview on the function of different receptor classes in animal host-microbiota communication. We put a special focus on invertebrate hosts, including both traditional invertebrate models such as Drosophila melanogaster and Caenorhabditis elegans and "non-model" invertebrates in microbiota research. Finally, we highlight the potential of invertebrate systems in studying mechanism of host-microbiota interactions. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) are a class of immune sensors that play a critical role in detecting and responding to several conserved patterns of microorganisms. As such, they play a major role in the maintenance of immune homeostasis and anti-microbial defense. Fundamental knowledge pertaining to the discovery of PRR functions and their ligands continue to advance the understanding of immune system and disease resistance, which led to the rational design and/or application of various PRR ligands as vaccine adjuvants. In addition, the conserved nature of many PRRs throughout the animal kingdom has enabled the utilization of the comparative genomics approach in PRR identification and the study of evolution, structural features, and functions in many animal species including avian. In the present review, we focused on PRR sensing and signaling functions in the avian species, domestic chicken, mallard, and domestic goose. In addition to summarizing recent advances in the understanding of avian PRR functions, the present review utilized a comparative biology approach to identify additional PRRs, whose functions have been well studied in mammalians but await functional characterization in avian. [ABSTRACT FROM AUTHOR]

Subclinical endometritis (SE) is one cause of repeat breeder syndrome (RBS). When endometrial cells come into contact with antigens during inflammatory events like endometritis, they act like innate immune system cells. Ovsynch-based therapies stimulate the innate immune system, which is how they may be able to cure SE and then RBS. This study aimed to assess the effects of presynch-10 and ovsynch applications on mRNA expressions of some endometrial Toll- and Nod-like receptors (TLRs and NLRs) in cows with RBS. A total of 40 repeat breeder cows were used in the study. The presynch-10 and ovsynch protocols were used in group 1 (G1, n=20), and no protocol was used in group 2 (G2, n=20). Endometrial samples were collected before and after the synchronization protocols in G1. In G2, samples were collected, and after waiting time up to the duration of synchronization protocol in G1, samples were taken again. The expression profiles of the genes being investigated were examined using RT-qPCR. NLRC4, NALP3 and TLR4 were basically expressed in all of the samples while NOD2 expression was completely undetectable. There was a statistical difference when NOD1 and TLR2 expressions in the second samples were compared between G1 and G2 (P<0.05). It was concluded that presynch-10 and ovsynch administration in cows may have a positively effect on the innate immune response and so be effective in the treatment of SE. [ABSTRACT FROM AUTHOR]

Galectins, as members of lectin families, exhibit a high affinity for β-galactosides and play diverse roles in biological processes. They function as pattern recognition receptors (PRRs) with important roles in immune defense. In this study, galectin-1, designated as SpGal-1, was identified and characterized from silver pomfret (Pampus argenteus). The SpGal-1 comprises an open reading frame (ORF) spanning 396 base pairs (bp) and encodes a deduced amino acid (aa) sequence containing a single carbohydrate recognition domain (CRD). Sublocalization analysis revealed that SpGal-1 was mainly expressed in the cytoplasm. The mRNA transcripts of SpGal-1 were ubiquitously detected in various tissues, with a higher expression level in the intestine. In addition, when exposed to Photobacterium damselae subsp. damselae (PDD) infection, both the liver and head kidney exhibited significantly increased SpGal-1 mRNA expression. The recombinant protein of SpGal-1 (named as rSpGal-1) demonstrated hemagglutination against red blood cells (RBCs) from Larimichthys crocea and P. argenteus in a Ca2+ or β-Mercaptoethanol (β-ME)-independent manner. Notably, rSpGal-1 could bind with various pathogen-associated molecular patterns (PAMPs) including D-galactose, D-mannose, lipopolysaccharide (LPS), and peptidoglycan (PGN), with highest affinity to PGN. Moreover, rSpGal-1 effectively interacted with an array of bacterial types encompassing Gram-positive bacteria (Staphylococcus aureus and Nocardia seriolae) and Gram-negative bacteria (PDD and Escherichia coli, among others), with the most robust binding affinity towards PDD. Collectively, these findings highlight that SpGal-1 is a crucial PRR with involvement in the host immune defense of silver pomfret. • Galectin-1, designated as SpGal-1, was identified and characterized from Pampus argenteus. • The rSpGal-1 demonstrated hemagglutination against RBCs from Larimichthys crocea and P. argenteus. • The rSpGal-1 could bind with various pathogen-associated molecular patterns (PAMPs) and an array of bacterial types. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Neutrophils uptake Leishmania promastigotes and tolerate amastigote differentiation. • During early infection, parasites do not seem to signal through neutrophil PRRs. • Visceral and cutaneous species of Leishmania activate neutrophil oxidative burst. • The extracellular activity of neutrophil enzymes is dependent on parasite species. • Neutrophils emit NETs against cutaneous and visceral species of Leishmania. Abstract Neutrophils are short-lived phagocytic cells equipped with several receptors for pathogen recognition and phagocytosis and have intracellular and extracellular effector mechanisms that can inactivate pathogens. Leishmaniases are diseases caused by different species of Leishmania that mainly afflicts poorer populations of tropical and subtropical regions and immunocompromised individuals. Thus, the present study aims to investigate the effector response of murine neutrophils to species of Leishmania causing American cutaneous leishmaniasis and zoonotic visceral leishmaniasis by evaluating pattern recognition receptors (PRR) and intracellular and extracellular effector microbicide activity. When exposed to Leishmania parasites, mouse neutrophils produced superoxide, released enzymes in the extracellular space and generated neutrophil extracellular traps, although PRR gene expression is negatively regulated. L. infantum , L. guyanensis , and L. shawi inhibited enzymatic activity, whereas L. amazonensis reduced the emission of extracellular structures. These findings indicate that although neutrophils trigger several microbicide mechanisms, Leishmania parasites can manipulate extracellular effector mechanisms. The present study also provides evidence that neutrophils can internalize parasites by coiling phagocytosis. [ABSTRACT FROM AUTHOR]

In the current concept of bacterial infections, pathogen-associated molecular patterns (PAMPs) derived from pathogens and damage-associated molecular patterns (DAMPs) released from damaged/necrotic host cells are crucial factors in induction of innate immune responses. However, the implication of DAMPs in apical and marginal periodontitis is unknown. Serum amyloid A (SAA) is a DAMP that is involved in the development of various chronic inflammatory diseases, such as rheumatoid arthritis. In the present study, we tested whether SAA is involved in the pathogenesis of periapical lesions, using human periapical surgical specimens and mice deficient in SAA and Toll-like receptors (TLR). SAA1/2 was locally expressed in human periapical lesions at the mRNA and protein levels. The level of SAA protein appeared to be positively associated with the inflammatory status of the lesions. In the development of mouse periapical inflammation, SAA1.1/2.1 was elevated locally and systemically in wild-type (WT) mice. Although SAA1.1/2.1 double-knockout and SAA3 knockout mice had redundant attenuation of the extent of periapical lesions, these animals showed strikingly improved inflammatory cell infiltration versus WT. Recombinant human SAA1 (rhSAA1) directly induced chemotaxis of WT neutrophils in a dose-dependent manner in vitro. In addition, rhSAA1 stimulation significantly prolonged the survival of WT neutrophils as compared with nonstimulated neutrophils. Furthermore, rhSAA1 activated the NF-κB pathway and subsequent IL-1α production in macrophages in a dose-dependent manner. However, TLR2/TLR4 double deficiency substantially diminished these SAA-mediated proinflammatory responses. Taken together, the SAA-TLR axis plays an important role in the chronicity of periapical inflammation via induction of inflammatory cell infiltration and prolonged cell survival. The interactions of PAMPs and DAMPs require further investigation in dental/oral inflammation. [ABSTRACT FROM AUTHOR]

Despite a global effort to develop an effective vaccine, malaria is still a significant health problem. Much of the pathology of malaria is immune mediated. This suggests that host immune responses have to be finely regulated. The innate immune system initiates and sets the threshold of the acquired immune response and determines the outcome of the disease. Yet, our knowledge of the regulation of innate immune responses during malaria is limited. Theoretically, inadequate activation of the innate immune system could result in unrestrained parasite growth. Conversely, hyperactivation of the innate immune system, is likely to cause excessive production of proinflammatory cytokines and severe pathology. Toll-like receptors (TLRs) have emerged as essential receptors which detect signature molecules and shape the complex host response during malaria infection. This review will highlight the mechanisms by which Plasmodium components are recognized by innate immune receptors with particular emphasis on TLRs. A thorough understanding of the complex roles of TLRs in malaria may allow the delineation of pathological versus protective host responses and enhance the efficacy of anti-malarial treatments and vaccines. [ABSTRACT FROM AUTHOR]

This review attempts to cover the implication of the toll-like receptors (TLRs) in controlling immune functions with emphasis on their significance, function, regulation and expression patterns. The tripartite TLRs are type I integral transmembrane receptors that are involved in recognition and conveying of pathogens to the immune system. These paralogs are located on cell surfaces or within endosomes. The TLRs are found to be functionally involved in the recognition of self and non-self-antigens, maturation of DCs and initiation of antigen-specific adaptive immune responses as they bridge the innate and adaptive immunity. Interestingly, they also have a significant role in immunotherapy and vaccination. Signals generated by TLRs are transduced through NFκB signaling and MAP kinases pathway to recruit pro-inflammatory cytokines and co-stimulatory molecules, which promote inflammatory responses. The excess production of these cytokines leads to grave systemic disorders like tumor growth and autoimmune disorders. Hence, regulation of the TLR signaling pathway is necessary to keep the host system safe. Many molecules like LPS, SOCS1, IRAK1, NFκB, and TRAF3 are involved in modulating the TLR pathways to induce appropriate response. Though quantification of these TLRs helps in correlating the magnitude of immune response exhibited by the animal, there are several internal, external, genetic and animal factors that affect their expression patterns. So it can be concluded that any identification based on those expression profiles may lead to improper diagnosis during certain conditions. [ABSTRACT FROM AUTHOR]

Innate immune system dysfunction has been known to be a key player in preeclampsia (PE). Activation of the maternal innate immunity may be triggered by invading microorganisms or endogenous ligands, which are detected by different pattern recognition receptors (PRRs). Although some studies have linked PRR activation to PE, it is still unclear if dysregulated PRR expression is associated with the development of this complication. Therefore, we conducted a systematic review of the literature, searching articles that evaluated associations of PRRs with PE. Twenty-six studies met the inclusion criteria: 20 of them analyzed PRR expressions and 6 studies investigated the association between PRR polymorphisms and PE. Among the PRRs, only few studies analyzed retinoic acid–inducible gene I-like helicase (RLH) and/or toll-like receptor (TLR)-1, 5, 6, 7, 8, and 9 expressions in immune cells or placentas from women with PE and controls; thus, it is inconclusive if these PRRs are involved in PE. Results from the 10 studies that analyzed TLR-2 expressions in women with PE and controls are also contradictory. The majority of the studies that investigated TLR-3 and -4 expressions indicate that these PRRs are increased in placenta or immune cells from women with PE compared to pregnant control woman. To date, polymorphisms in TLR-2, -3, and -4 and nucleotide-binding oligomerization domain-like receptor 2 genes do not seem to be associated with PE development. No study has evaluated the association between polymorphisms in genes codifying other TLRs or RLHs genes. In conclusion, available data in literature support a role for TLR-3 and TLR-4 in the pathogenesis of PE. [ABSTRACT FROM AUTHOR]

The innate immune system is the first line of defense against virus infection that triggers the expression of type I interferon (IFN) and proinflammatory cytokines. Pattern recognition receptors (PRRs) recognize pathogen-associated molecular patterns, resulting in the induction of innate immune responses. Viral RNA in endosomes is recognized by Toll-like receptors, and cytoplasmic viral RNA is recognized by RIG-I-like receptors. The host innate immune response is critical for protection against virus infection. However, it has been postulated that an excessive inflammatory response in the lung caused by the innate immune response is harmful to the host and is a cause of lethality during influenza A virus infection. Although the deletion of genes encoding PRRs or proinflammatory cytokines does not improve the mortality of mice infected with influenza A virus, a partial block of the innate immune response is successful in decreasing the mortality rate of mice without a loss of protection against virus infection. In addition, morbidity and mortality rates are influenced by other factors. For example, secondary bacterial infection increases the mortality rate in patients with influenza A virus and in animal models of the disease, and environmental factors, such as cigarette smoke and fine particles, also affect the innate immune response. In this review, we summarize recent findings related to the role of PRRs in innate immune response during respiratory viral infection. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by T cell-mediated destruction of the insulin-producing pancreatic β cells. A combination of genetic and environmental factors eventually leads to the loss of functional β cell mass and hyperglycemia. Both innate and adaptive immunity are involved in the development of T1D. In this review, we have highlighted the most recent findings on the role of innate immunity, especially the pattern recognition receptors (PRRs), in disease development. In murine models and human studies, different PRRs, such as toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat-containing (or Nod-like) receptors (NLRs), have different roles in the pathogenesis of T1D. These PRRs play a critical role in defending against infection by sensing specific ligands derived from exogenous microorganisms to induce innate immune responses and shape adaptive immunity. Animal studies have shown that TLR7, TLR9, MyD88 and NLPR3 play a disease-predisposing role in T1D, while controversial results have been found with other PRRs, such as TLR2, TLR3, TLR4, TLR5 and others. Human studies also shown that TLR2, TLR3 and TLR4 are expressed in either islet β cells or infiltrated immune cells, indicating the innate immunity plays a role in β cell autoimmunity. Furthermore, some human genetic studies showed a possible association of TLR3, TLR7, TLR8 or NLRP3 genes, at single nucleotide polymorphism (SNP) level, with human T1D. Increasing evidence suggest that the innate immunity modulates β cell autoimmunity. Thus, targeting pathways of innate immunity may provide novel therapeutic strategies to fight this disease. [ABSTRACT FROM AUTHOR]

Objective Human aging is associated with remodeling of the immune system. While most studies on immunosenescence have focused on adaptive immunity, the effects of aging on innate immunity are not well understood. Here, we investigated whether aging affects cytokine responses to a wide range of well-defined pattern recognition receptor (PRR) ligands, such as ligands for Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), retinoic-acid-inducible gene-I like receptors (RLRs) and the cytosolic DNA sensor absent in melanoma 2 (AIM2). Method Blood was collected from 16 young (20–39 years) and 18 elderly (60–84 years) healthy participants. Pro-inflammatory cytokine (TNF-α, IL-1β, IL-6, and IL-8) production in a whole blood assay (WBA) after stimulation with TLR ligands (Pam3csk4, poly(I:C), LPS, CpG), CLR ligand (β-glucan), NLR ligand (MDP), RLR ligands (5′ppp-dsDNA and poly(I:C)/lyovec) and the AIM2 ligand (poly(dA:dT) was assessed by ELISA. TLR2 and TLR4 expression by leukocytes and monocytes was determined by flow-cytometry. Expression of AIM2 by peripheral blood mononuclear cells (PBMC) was assessed by qRT-PCR and Western blot. Result Cytokine responses to Pam3csk4, poly(I:C) and CpG, β-glucan, MDP, 5′ppp-dsDNA and poly(I:C)/lyovec were comparable between young and old participants. We observed a higher IL-8 response following stimulation of elderly blood samples with the TLR4 ligand LPS, which was associated with higher proportions of TLR4 expressing monocytes. Interestingly, stimulation of whole blood cells with the AIM2 ligand poly(dA:dT) resulted in significantly lower cytokine responses in old participants. Moreover, these lower cytokine responses were associated with lower AIM2 protein expression and activation in PBMC of old participants. Conclusion Our findings reveal an age-dependent reduction of AIM2 expression and activation which may explain reduced cytokine responses to the cytosolic DNA mimic poly(dA:dT) in healthy elderly individuals. Reduced AIM2-mediated sensing with age may contribute to increased vulnerability to bacterial or viral infections in the elderly. [ABSTRACT FROM AUTHOR]

Alphaviruses are a family of positive-strand RNA viruses that circulate on all continents between mosquito vectors and vertebrate hosts. Despite a significant public health threat, their biology is not sufficiently investigated, and the mechanisms of alphavirus replication and virus–host interaction are insufficiently understood. In this study, we have applied a variety of experimental systems to further understand the mechanism by which infected cells detect replicating alphaviruses. Our new data strongly suggest that activation of the antiviral response by alphavirus-infected cells is determined by the integrity of viral genes encoding proteins with nuclear functions, and by the presence of two cellular pattern recognition receptors (PRRs), RIG-I and MDA5. No type I IFN response is induced in their absence. The presence of either of these PRRs is sufficient for detecting virus replication. However, type I IFN activation in response to pathogenic alphaviruses depends on the basal levels of RIG-I or MDA5. [ABSTRACT FROM AUTHOR]

Pathogen recognition induces the production of reactive oxygen species (ROS) by NADPH oxidases in both plants and animals. ROS have direct antimicrobial properties, but also serve as signaling molecules to activate further immune outputs. However, ROS production has to be tightly controlled to avoid detrimental effects on host cells, but yet must be produced in the right amount, at the right place and at the right time upon pathogen perception. Plant NADPH oxidases belong to the respiratory burst oxidase homolog (RBOH) family, which contains 10 members in the model plant Arabidopsis thaliana. The perception of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) leads to a rapid, specific and strong production of ROS, which is dependent on RBOHD. RBOHD is mainly controlled by Ca2+ via direct binding to EFhand motifs and phosphorylation by Ca2+-dependent protein kinases. Recent studies have, however, revealed a critical role for a Ca2+-independent regulation of RBOHD. The plasma membrane-associated cytoplasmic kinase BIK1 (BOTRYTIS-INDUCED KINASE1), which is a direct substrate of the PRR complex, directly interacts with and phosphorylates RBOHD upon PAMP perception. Impairment of these phosphorylation events completely abolishes the function of RBOHD in immunity. These results suggest that RBOHD activity is tightly controlled by multilayered regulations. In this review, we summarize recent advances in our understanding of the regulatory mechanisms controlling RBOHD activation. [ABSTRACT FROM AUTHOR]

Nucleic acid-based therapeutics have gained increased attention during recent decades because of their wide range of application prospects. Immunostimulatory nucleic acids represent a promising class of potential drugs for the treatment of tumoral and viral diseases due to their low toxicity and stimulation of the body's own innate immunity by acting on the natural mechanisms of its activation. The repertoire of nucleic acids that directly interact with the components of the immune system is expanding with the improvement of both analytical methods and methods for the synthesis of nucleic acids and their derivatives. Despite the obvious progress in this area, the problem of delivering therapeutic acids to target cells as well as the unresolved issue of achieving a specific therapeutic effect based on activating the mechanism of interferon and anti-inflammatory cytokine synthesis. Minimizing the undesirable effects of excessive secretion of inflammatory cytokines remains an unsolved task. This review examines recent data on the types of immunostimulatory nucleic acids, the receptors interacting with them, and the mechanisms of immunity activation under the action of these molecules. Finally, data on immunostimulatory nucleic acids in ongoing and completed clinical trials will be summarized. [ABSTRACT FROM AUTHOR]

The pattern recognition receptors, complement system, inflammasomes, antimicrobial peptides, and cytokines are innate immunity soluble factors. They sense, either directly or indirectly, the potential threats and produce inflammation and cellular death. High interest in their modulation has emerged lately, acknowledging they are involved in many cutaneous inflammatory, infectious, and neoplastic disorders. We extensively reviewed the implication of soluble factors in skin innate immunity. Furthermore, we showed which molecules target these factors, how these molecules work, and how they have been used in dermatological practice. Cytokine inhibitors have paved the way to a new era in treating moderate to severe psoriasis and atopic dermatitis. [ABSTRACT FROM AUTHOR]

Host cell-intrinsic antiviral responses are largely mediated by pattern-recognition receptor (PRR) signaling and the interferon (IFN) system. The IFN regulatory factor (IRF) family of transcription factors takes up a central role in transcriptional regulation of antiviral innate immunity. IRF3 and IRF7 are known to be key players downstream of PRRs mediating the induction of type I and III IFNs. IFN signaling then requires IRF9 for the expression of the full array of interferon stimulated genes (ISGs) ultimately defining the antiviral state of the cell. Other members of the IRF family clearly play a role in mediating or modulating IFN responses, such as IRF1, IRF2 or IRF5, however their relative contribution to mounting a functional antiviral response is much less understood. In this study, we systematically and comparatively assessed the impact of six members of the IRF family on antiviral signaling in alveolar epithelial cells. We generated functional knockouts of IRF1, -2, -3, -5, -7, and -9 in A549 cells, and measured their impact on the expression of IFNs and further cytokines, ISGs and other IRFs, as well as on viral replication. Our results confirmed the vital importance of IRF3 and IRF9 in establishing an antiviral state, whereas IRF1, 5 and 7 were largely dispensable. The previously described inhibitory activity of IRF2 could not be observed in our experimental system. [ABSTRACT FROM AUTHOR]

Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence. In this review, we compare elements of phagocytosis in mammals and the nematode Caenorhabditis elegans. Initial recognition of infection requires different mechanisms. In mammals, pattern recognition receptors bind pathogens directly, whereas activation of the innate immune response in the nematode rather relies on the detection of cellular damage. In contrast, molecules involved in efferocytosis—the engulfment and elimination of dying cells and cell debris—are highly conserved between the two species. Therefore, C. elegans is a powerful model to research mechanisms of the phagocytic machinery. Finally, we show that both mammalian and worm studies help to understand how the two phagocytic functions are interconnected: emerging data suggest the activation of innate immunity as a consequence of defective apoptotic cell clearance. [ABSTRACT FROM AUTHOR]

Fibrinogen-related proteins (FREPs) that contain only the fibrinogen-related domain are likely involved in pathogen recognition. In this study, we identified two FREPs from the razor clam (Sinonovacula constricta), called ScFREP-1 and ScFREP-2, and investigated their roles in the immune response. Both ScFREP-1 and ScFREP-2 contained a fibrinogen-related domain at the C-terminal. ScFREP-1 and ScFREP-2 mRNAs were detected in all adult clam tissues tested, with the highest expression levels in the gill and mantle, respectively. Their expression levels were significantly upregulated after microbe infection. Recombinant ScFREPs could bind Gram-positive and Gram-negative bacteria as well as some pathogen-associated molecular patterns (PAMPs), and they could agglutinate those bacteria. These results showed that ScFREPs functioned as potential pattern recognition receptors to mediate immune response by recognizing PAMPs and agglutinating invasive microbes. • Two fibrinogen-related proteins from the razor clam Sinonovacula constricta. • Exploring their roles in immune defense as potential pattern recognition receptors. • Identification of pathogen-associated molecular patterns. [ABSTRACT FROM AUTHOR]

The majority of current cancer immunotherapy strategies target and potentiate antitumor adaptive immune responses. Unfortunately, the efficacy of these treatments has been limited to a fraction of patients within a subset of tumor types, with an aggregate response rate of approximately 20% to date across all malignancies. The success of therapeutic inhibition of programmed death protein 1 (PD-1), protein death ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) with immune checkpoint inhibitors (ICI) has been limited to "hot" tumors characterized by preexisting T cell infiltration, whereas "cold" tumors, which lack T cell infiltration, have not achieved durable benefit. There are several mechanisms by which "cold" tumors fail to generate spontaneous immune infiltration, which converge upon the generation of an immunosuppressive tumor microenvironment (TME). The role of the innate immune system in tumor immunosurveillance and generation of antitumor immune responses has been long recognized. In recent years, novel strategies to target innate immunity in cancer therapy have emerged, including therapeutic stimulation of pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs); the DNA sensing cGAS/STING pathway; nucleotide-binding oligomerization domain-like receptors (NLRs), such as NLRP3; and the retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs). In addition, therapeutic modulation of key innate immune cell types, such as macrophages and natural killer cells, has been investigated. Herein, we review therapeutic approaches to activate innate immunity within the TME to enhance antitumor immune responses, with the goal of disease eradication in "cold" tumors. In addition, we discuss rational immune-oncology combination strategies that activate both innate and adaptive immunity, with the potential to enhance the efficacy of current immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Pattern recognition receptors (PRRs) and inflammasomes are a key part of the anti-viral innate immune system as they detect conserved viral pathogen-associated molecular patterns (PAMPs). A successful host response to viral infections critically depend on the initial activation of PRRs by viruses, mainly by viral DNA and RNA. The signalling pathways activated by PRRs leads to the expression of pro-inflammatory cytokines, to recruit immune cells, and type I and type III interferons which leads to the induction of interferon stimulated genes (ISG), powerful virus restriction factors that establish the "antiviral state". Inflammasomes contribute to anti-viral responses through the maturation of interleukin (IL)-1 and IL-18 and through triggering pyroptotic cell death. The activity of the innate immune system along with the adaptive immune response normally leads to successful virus elimination, although disproportionate innate responses contribute to viral pathology. In this review we will discuss recent insights into the influence of PRR activation and inflammasomes on viral infections and what this means for the mammalian host. We will also comment on how specific PRRs and inflammasomes may be relevant to how SARS-CoV-2, the virus responsible for the current COVID-19 pandemic, interacts with host innate immunity. [ABSTRACT FROM AUTHOR]

• PRR expression on monocytes and neutrophils is diminished early after pediatric CPB. • Single dose methylprednisolone affects cytokine response but not PRR expression. • Intermediate monocytes exhibit higher levels of TLR2, TLR4 and CD64 after CPB. • TLR4 upregulation on intermediate monocytes correlates with poorer clinical course. Congenital heart surgery with cardiopulmonary bypass (CPB) initiates an immune response which frequently leads to organ dysfunction and a systemic inflammatory response. Complications associated with exacerbated immune responses may severely impact the postoperative recovery. The objective was to describe the characteristics of monocyte subpopulations and neutrophils at the level of pattern recognition receptors (PRR) and the cytokine response after CPB in infants. An observational cohort study was conducted between June 2016 and June 2017 of infants < 2 years of age, electively admitted for surgical correction of acyanotic congenital heart defects using CPB. Fourteen blood samples were collected sequentially and processed immediately during and up to 48 h following cardiac surgery for each patient. Flow cytometry analysis comprised monocytic and granulocytic surface expression of CD14, CD16, CD64, TLR2, TLR4 and Dectin-1 (CLEC7A). Monocyte subpopulations were further defined as classical (CD14++/CD16−), intermediate (CD14++/CD16+) and nonclassical (CD14+/CD16++) monocytes. Plasma concentrations of 14 cytokines, including G-CSF, GM-CSF, IL-1β, IL-1RA, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, TNF-α, IFN-γ, MIP-1β (CCL4) and TGF-β1, were measured using multiplex immunoassay for seven points in time. Samples from 21 infants (median age 7.4 months) were analyzed by flow cytometry and from 11 infants, cytokine concentrations were measured. Classical and intermediate monocytes showed first receptor upregulation with an increase in CD64 expression four hours post CPB. CD64–expression on intermediate monocytes almost tripled 48 h post CPB (p < 0.0001). TLR4 was only increased on intermediate monocytes, occurring 12 h post CPB (p = 0.0406) along with elevated TLR2 levels (p = 0.0002). TLR4 expression on intermediate monocytes correlated with vasoactive-inotropic score (r s = 0.642, p = 0.0017), duration of ventilation (r s = 0.485, p = 0.0259), highest serum creatinine (r s = 0.547, p = 0.0102), postsurgical transfusion (total volume per kg bodyweight) (r s = 0.469, p = 0.0321) and lowest mean arterial pressure (r s = -0.530, p = 0.0135). Concentrations of IL-10, MIP-1β, IL-8, G–CSF and IL-6 increased one hour post CPB. Methylprednisolone administration in six patients had no significant influence on the studied surface receptors but led to lower IL-8 and higher IL-10 plasma concentrations. Congenital heart surgery with CPB induces a systemic inflammatory process including cytokine response and changes in PRR expression. Intermediate monocytes feature specific inflammatory characteristics in the 48 h after pediatric CPB and TLR4 correlates with poorer clinical course, which might provide a potential diagnostic or even therapeutic target. [ABSTRACT FROM AUTHOR]

The innate immune system consists of a variety of elements controlling and participating in virtually all aspects of inflammation and immunity. It is crucial for host defense, but on the other hand its improper activation is also thought to be responsible for the generation of autoimmunity and therefore diseases such as autoimmune arthritides like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS) or inflammatory bowel disease. The innate immune system stands both at the beginning as well as the end of autoimmunity. On one hand, it regulates the activation of the adaptive immune system and the breach of self-tolerance, as antigen presenting cells (APCs), especially dendritic cells, are essential for the activation of naïve antigen specific T cells, a crucial step in the development of autoimmunity. Various factors controlling the function of dendritic cells have been identified that directly regulate lymphocyte homeostasis and in some instances the generation of organ specific autoimmunity. Moreover, microbial cues have been identified that are prerequisites for the generation of several specific autoimmune diseases. On the other hand, the innate immune system is also responsible for mediating the resulting organ damage underlying the clinical symptoms of a given autoimmune disease via production of proinflammatory cytokines that amplify local inflammation and further activate other immune or parenchymal cells in the vicinity, the generation of matrix degrading and proteolytic enzymes or reactive oxygen species directly causing tissue damage. In the last decades, molecular characterization of cell types and their subsets as well as both positive and negative regulators of immunity has led to the generation of various scenarios of how autoimmunity develops, which eventually might lead to the development of targeted interventions for autoimmune diseases. In this review, we try to summarize the elements that are contributing to the initiation and perpetuation of autoimmune responses. • Antigen presenting cells are crucial for the initiation of systemic autoimmunity. • A multitude of endogenous factors regulates autoimmunity and the breach of self-tolerance in APCs. • The microbiome profoundly influences the development of autoimmunity. • Pattern recognition receptors such as Toll-like receptors integrate exogenous (microbial) and endogenous signals. [ABSTRACT FROM AUTHOR]

• A sheep C-type lectin receptor (CTLR)-Fc fusion protein library was established. • This novel library is a tool to screen for CTLR interactions with sheep pathogens. • Several ovine CTLRs share ligand preferences with the respective murine orthologs. • The utility of the CTLR-Fc library was tested with Mycoplasma mycoides subsp. capri. C-type lectin receptors (CTLRs) are pattern recognition receptors which are important constituents of the innate immunity. However, their role has mostly been studied in humans and in mouse models. To bridge the knowledge gap concerning CTLRs of veterinary relevant species, a novel ovine CTLR hFc-fusion protein library which allows in vitro ligand identification and pathogen binding studies has been established. Its utility was tested with known ligands of corresponding murine CTLRs in ELISA- and flow cytometry based binding studies. The ovine CTLR-hFc library was subsequently used in a proof-of-principle pathogen binding study with the ruminant pathogen Mycoplasma mycoides subsp. capri. Some ovine CTLRs, such as Dendritic Cell Immunoreceptor (DCIR, Clec4a), Macrophage C-Type Lectin (MCL, Clec4d) and Myeloid Inhibitory C-Type Lectin-Like Receptor (MICL, Clec12a) were identified as possible candidate receptors whose role in Mycoplasma recognition can now be unraveled in further studies. This study thus shows the utility of this novel ovine CTLR-hFc fusion protein library to screen for CTLR/pathogen interactions. [ABSTRACT FROM AUTHOR]

The innate immune system identifies exogenous threats or endogenous stress through germline-encoded receptors called pattern recognition receptors (PRRs) that initiate consecutive downstream signaling pathways to control immune responses. However, the contribution of the immune system and inflammation to fibrosing interstitial lung diseases (ILD) remains poorly understood. Immunoreceptor tyrosine-based motif-bearing C-type lectin-like receptors (CTLRs) may interact with various immune cells during tissue injury and wound repair processes. Dectin-1 is a CTLR with dominant mechanisms manifested through its intracellular signaling cascades, which regulate fibrosis-promoting properties through gene transcription and cytokine activation. Additionally, immune impairment in ILD facilitates microbiome colonization; hence, Dectin-1 is the master protector in host pulmonary defense against fungal invasion. Recent progress in determining the signaling pathways that control the balance of fibrosis has implicated immunoreceptor tyrosine-based motif-bearing CTLRs as being involved, either directly or indirectly, in the pathogenesis of fibrosing ILD. [ABSTRACT FROM AUTHOR]

Insects, which lack the adaptive immune system, have developed sophisticated innate immune system consisting of humoral and cellular immune responses to defend against invading microorganisms. Non-self recognition of microbes is the front line of the innate immune system. Repertoires of pattern recognition receptors (PRRs) recognize the conserved pathogen-associated molecular patterns (PAMPs) present in microbes, such as lipopolysaccharide (LPS), peptidoglycan (PGN), lipoteichoic acid (LTA) and β-1, 3-glucans, and induce innate immune responses. In this review, we summarize current knowledge of the structure, classification and roles of PRRs in innate immunity of the model organism Drosophila melanogaster , focusing mainly on the peptidoglycan recognition proteins (PGRPs), Gram-negative bacteria-binding proteins (GNBPs), scavenger receptors (SRs), thioester-containing proteins (TEPs), and lectins. • Summarize the structure, classification and roles of Drosophila PRRs in innate immunity. • The sensor PGRPs recognize different types of PGN to activate the immune signaling pathways. • The regulatory PGRPs modulate the binding of PGN to sensor PGRPs. • Scavenger receptors, thioester-containing proteins and lectins activate cellular immune responses. [ABSTRACT FROM AUTHOR]