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The NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18. NLRP3 is the most extensively studied inflammasome to date due to its array of activators and aberrant activation in several inflammatory diseases. Studies using small molecules and biologics targeting the NLRP3 inflammasome pathway have shown positive outcomes in treating various disease pathologies by blocking chronic inflammation. In this review, we discuss the recent advances in understanding the NLRP3 mechanism, its role in disease pathology, and provide a broad review of therapeutics discovered to target the NLRP3 pathway and their challenges. [ABSTRACT FROM AUTHOR]

Background and Aim: The reports from the Ministry of Agriculture and Fisheries suggest that camels suffer less compared to goats, sheep, and cows from a number of common infectious diseases in Oman. However, there is no immunological evidence to substantiate this claim. This present study is, therefore, an attempt to study the immunological responses of camels, goats, sheep, and cows by comparing their oxidative respiratory burst of peripheral blood leukocytes (PBLs) as a marker of innate immunity occurring during phagocytosis and the mitogenic responses of their peripheral blood mononuclear leukocytes (PBMLs) as a marker of their adaptive immune response. Materials and Methods: Ten female adult animals (n = 10) were selected from each species (goats, sheep, and cows). The goats, sheep, and cows were maintained at the Agricultural Experiment Station, while camels were kept at the Royal Camel Corps (RCC). Blood samples were collected from the jugular vein in 7 mL of heparin and ethylenediaminetetraacetic acid vacutainer tubes. The oxidative respiratory burst of PBLs was measured using a chemiluminescence (CL) assay. Reactants consisted of 75 µL of whole blood diluted (1:50), 75 µL of luminol/isoluminol, and 75 µL of zymosan opsonized with nonheat inactivated serum/heat-inactivated serum or non-opsonized zymosan. CL responses were measured as relative light units and expressed as the mean count per minute and peak CL values. The mitogenic response of PBMLs to concanavalin A (Con-A), phytohemagglutinin (PHA), and pokeweed mitogen (PWM) was tested using a WST-8 assay and read spectrophotometrically at 450 nm. Results: The present findings showed that camel PBLs generate significantly higher CL responses, both intracellularly as well as extracellularly, with zymosan opsonized with autologous serum. Camel PBLs demonstrated a significantly higher (p = 0.001) response when stimulated with zymosan opsonized with heat-inactivated serum compared to those of goat, sheep, and cow lymphocytes from camels exhibited significantly higher (p = 0.001) stimulation indices (SI) with Con-A, PHA, and PWM. Conclusion: The present study suggests that camels are capable of mounting both superior innate as well as adaptive immune responses and provide immunological evidence supporting the belief of some authors, who have proposed that camels are less susceptible to a number of common infectious diseases than other domesticated ruminants. [ABSTRACT FROM AUTHOR]

Lead (Pb) is one of the most common metals found in ecosystems in elevated concentrations derived mainly from anthropogenic activities. Pb toxicity is of special concern in birds due to its capacity for bioaccumulation in the liver, bones, and kidneys causing physiological disruptions. Such disruptions can be lethal in a few days after Pb acute intoxication and they are associated with several million deaths of birds. Moreover, Pb may work as an immunosuppressant as it affects the cell‐mediated and humoral immune responses, including components of the acute‐phase response (APR). We (1) examined the effects of Pb contamination on the innate immune system, body mass, and food intake of Japanese quails (Coturnix coturnix japonica), and (2) evaluated the effects of Pb on its APR after exposing the animals to Pb acetate in drinkable water during 7 days. We found that Pb contamination increased the number of circulating white blood cells (WBCs), but no effect was found on body mass, food intake, the heterophil/lymphocyte (H/L) ratio, and haptoglobin (Hp) concentration. When Pb‐exposed birds were injected with lipopolysaccharide from Escherichia coli to activate the APR, they had a negative body mass ratio, reduced food intake, and increased the number of WBCs, the H/L ratio, and the Hp concentration. We conclude that Pb exposure at this dose did not affect baseline values of the constitutive response and that it did not affect the APR of quails, but commend for further studies testing the effect of different Pb doses. Research Highlights: Pb did not depress baseline values of quail's cellular and humoral innate immunity.Pb exposure did not reduce body mass and food intake, nor increase the H/L, a proxy of stress.Lead exposure did not depress the acute‐phase response of quails. [ABSTRACT FROM AUTHOR]

l‐Theanine (N‐ethyl‐ l‐glutamine) is an analog of l‐glutamine and l‐glutamic acid, accounts for up to 50% of all free amino acids in green tea, and elicits an umami taste. As l‐theanine also shows various physiological activities including immune response‐modifying activities, it is expected to be an excellent health‐promoting phytochemical agent. To know the influences of l‐theanine on the human innate immune response, we investigated the effect of l‐theanine on the superoxide anion (O2−)‐generating system of leukocytes using U937 cells. The O2−‐generating system in leukocytes consists of membrane cytochrome b558 protein (a complex of p22‐phox and gp91‐phox proteins) and cytosolic p40‐phox, p47‐phox, and p67‐phox proteins. Addition of 500 μM l‐theanine caused remarkable enhancement of the all‐trans retinoic acid (ATRA)‐induced O2−‐generating activity (to ~470% of ATRA‐treated cells), but not l‐glutamine and l‐glutamic acid. Semiquantitative RT‐PCR showed that the transcription level of gp91‐phox is significantly increased in ATRA and l‐theanine‐co‐treated cells. Chromatin immunoprecipitation revealed that l‐theanine enhances acetylations of Lys‐9 and Lys‐14 residues of histone H3 within the chromatin surrounding the promoter region of the gp91‐phox gene. Immunoblotting demonstrated that membrane cytochrome b558 proteins remarkably accumulate in ATRA + l‐theanine‐treated cells. These results suggested that l‐theanine brings about a remarkable accumulation of cytochrome b558 protein via upregulating the transcription of the gp91‐phox gene during leukocyte differentiation, resulting in marked augmentation of the O2−‐generating ability, which is one of the most important functions of leukocytes responsible for the innate immune system. [ABSTRACT FROM AUTHOR]

The high proliferation of microorganisms in aquatic environments has allowed their coevolution for billions of years with other living beings that also inhabit these niches. Among the different existing types of interaction, the eternal competition for supremacy between the susceptible species and their pathogens has selected, as part of the effector division of the immune system of the former ones, a vast and varied arsenal of efficient antimicrobial molecules, which is highly amplified by the broad biodiversity radiated, above any others, at the marine habitats. At present, the great recent scientific and technological advances already allow the massive discovery and exploitation of these defense compounds for therapeutic purposes against infectious diseases of our interest. Among them, antimicrobial peptides and antimicrobial metabolites stand out because of the wide dimensions of their structural diversities, mechanisms of action, and target pathogen ranges. This revision work contextualizes the research in this field and serves as a presentation and scope identification of the Special Issue from Marine Drugs journal "The Immune System of Marine Organisms as Source for Drugs against Infectious Diseases". [ABSTRACT FROM AUTHOR]

Abstract Background Potato cyst nematodes belong to the most harmful pathogens in potato, and durable management of these parasites largely depends on host-plant resistances. These resistances are pathotype specific. The current Globodera rostochiensis pathotype scheme that defines five pathotypes (Ro1 - Ro5) is both fundamentally and practically of limited value. Hence, resistant potato varieties are used worldwide in a poorly informed manner. Results We generated two novel reference genomes of G. rostochiensis inbred lines derived from a Ro1 and a Ro5 population. These genome sequences comprise 173 and 189 scaffolds respectively, marking a ≈ 24-fold reduction in fragmentation as compared to the current reference genome. We provide copy number variations for 19 effector families. Four dorsal gland effector families were investigated in more detail. SPRYSECs, known to be implicated in plant defence suppression, constitute by far the most diversified family studied herein with 60 and 99 variants in Ro1 and Ro5 distributed over 18 and 26 scaffolds. In contrast, CLEs, effectors involved in feeding site induction, show strong physical clustering. The 10 and 16 variants cluster on respectively 2 and 1 scaffolds. Given that pathotypes are defined by their effectoromes, we pinpoint the disparate nature of the contributing effector families in terms of sequence diversification and loss and gain of variants. Conclusions Two novel reference genomes allow for nearly complete inventories of effector diversification and physical organisation within and between pathotypes. Combined with insights we provide on effector family-specific diversification patterns, this constitutes a basis for an effectorome-based virulence scheme for this notorious pathogen.

[Display omitted] • β-1–3-glucan (laminarin) has a potential as an immunostimulant. • THC is increased following the immune stimulation with CBS and β-1–3-glucan. • Domain organisation of C/EBP and Kr-h1 is conserved in freshwater crayfish. • C/EBP and Kr-h1 are ubiquitously expressed in all tested tissues. • Immune stimulation with β-1–3-glucan leads to C/EBP up-regulation. Transcription factors (TFs) have an important role in the regulation of the gene expression network. The role of TFs in the immune response of freshwater crayfish is poorly understood, but leveraging the regulatory mechanisms of immune response could augment the resistance against the invasive oomycete pathogen, Aphanomyces astaci. Previous studies indicated that the TFs CCAAT/enhancer-binding protein (C/EBP) and putative Krüppel homolog-1 protein (Kr-h1) might play a role in immune and stress response of the noble crayfish (Astacus astacus). Here, we aimed to further characterise these two gene products to gain a better understanding of their evolutionary origin, domain organisation and expression patterns across different crayfish tissues. Furthermore, we conducted an immune stimulation experiment to observe the potential changes in the gene expression of C/EBP and Kr-h1 under immune challenge in different crayfish tissues. Our results showed that both C/EBP and Kr-h1 are closely related to other C/EBP s and Kr-h1 s in Malacostraca. Gene expression analysis revealed that both TFs are present in all analysed tissues, with higher expression of C/EBP in the gills and Kr-h1 in the abdominal muscle. Immune stimulation with laminarin (mimicking β-1–3-glucan in the oomycete cell wall) showed an activation of the crayfish immune system, with an overall increase in the total haemocyte count (THC) compared to untreated control and crayfish buffered saline (CBS) treatment. On the gene expression level, an up-regulation of the C/EBP gene was detected in the laminarin treated group in hepatopancreas and heart, while no changes were observed for the Kr-h1 gene. Our results indicate an early change in C/EBP expression in multiple tissues during immune stimulation and suggest its involvement in the immune response of the noble crayfish. [ABSTRACT FROM AUTHOR]

Liver cancer has become the second most deadly malignant disease, with no efficient targeted or immune therapeutic agents available yet. While dissecting the roles of cytoplasmic signaling molecules in hepatocarcinogenesis using an inducible mouse gene targeting system, Mx1-cre, we identified a potent liver tumor-inhibitory effect of synthetic double-stranded RNA (dsRNA), polyinosinic-polycytidylic acid (pIC), an inducer of the Mx1-cre system. Injection of pIC at the pre-cancer stage robustly suppressed liver tumorigenesis either induced by chemical carcinogens or by Pten loss and associated hepatosteatosis. The immunostimulatory dsRNA inhibited liver cancer initiation, apparently by boosting multiple anti-tumor activities of innate immunity, including induction of immunoregulatory cytokines, activation of NK cells and dendritic cells, and reprogramming of macrophage polarization. This study paves the way for the development of preventive and early interfering strategies for liver cancer to reduce the rapidly increasing incidences of liver cancer in an ever-growing population with chronic liver disorders.

BackgroundThe age-related loss of muscle mass significantly contributes to the development of chronic diseases, loss of mobility and dependency on others, yet could be improved by an optimized lifestyle.ObjectiveThe goal of this randomized controlled trial was to compare the influence of a habitual diet (CON) with either a diet containing the recommended protein intake (RP) or a high protein intake (HP), both with and without strength training, on the plasma proteome in older adults.MethodsOne hundred and thirty-six women and men (65–85 years) were randomly assigned to three intervention groups. CON continued their habitual diet; participants of the HP and RP group consumed either high protein or standard foods. After 6 weeks of dietary intervention, HP and RP groups additionally started a strength training intervention twice per week for 8 weeks. Twenty-four hours dietary recalls were performed every 7–10 days. Body composition was assessed and blood taken. Plasma proteomics were assessed with LC-MS.ResultsParticipants of the HP group doubled their baseline protein intake from 0.80 ± 0.31 to 1.63 ± 0.36 g/kg BW/d; RP increased protein intake from 0.89 ± 0.28 to 1.06 ± 0.26 g/kg BW/d. The CON group kept the protein intake stable throughout the study. Combined exercise and HP initiated notable changes, resulting in a reduction in bodyfat and increased muscle mass. Proteomics analyses revealed 14 significantly affected proteins by HP diet, regulating innate immune system, lipid transport and blood coagulation, yet the additional strength training did not elicit further changes.ConclusionsCombined HP and resistance exercise in healthy older adults seem to induce favorable changes in the body composition. Changes in the plasma proteome due to the high protein diet point to a beneficial impact for the innate immune system, lipid transport and blood coagulation system, all of which are involved in chronic disease development.Clinical trial registrationThe study was registered at ClinicalTrials.gov (NCT04023513).

The cytokine interleukin 1 (IL-1) is an evolutionary innovation of vertebrates. Fish and amphibian have one IL1 gene, while mammals have two copies of IL1, IL1A and IL1B, with distinct expression patterns and differences in their proteolytic activation. Our current understanding of the evolutionary history of IL-1 is mainly based on phylogenetic analysis, but this approach provides no information on potentially different functions of IL-1 homologues, and it remains unclear which biological activities identified for IL-1α and IL-1β in mammals are present in lower vertebrates. Here, we use in vitro and in vivo experimental models to examine the expression patterns and cleavage of IL-1 proteins from various species. We found that IL-1 in the teleost medaka shares the transcriptional patterns of mammalian IL-1α, and its processing also resembles that of mammalian IL-1α, which is sensitive to cysteine protease inhibitors specific for the calpain and cathepsin families. By contrast, IL-1 proteins in reptiles also include biological properties of IL-1β. Therefore, we propose that the duplication of the ancestral IL1 gene led to the segregation of expression patterns and protein processing that characterizes the two extant forms of IL-1 in mammals.

Selenophosphate synthetase 1 (SPS1) is an essential gene for the cell growth and embryogenesis in Drosophila melanogaster. We have previously reported that SPS1 deficiency stimulates the expression of genes responsible for the innate immune system, including antimicrobial peptides (AMPs), in Drosophila S2 cells. However, the underlying mechanism has not been elucidated. Here, we investigated the immune pathways that control the SPS1-deficiency-induced expression of AMPs in S2 cells. It was found that the activation of AMP expression is regulated by both immune deficiency (IMD) and the Toll pathway. Double knockdown of the upstream genes of each pathway with SPS1 showed that the peptidoglycan recognition protein-LC (PGRP-LC) and Toll genes are targeted by SPS1 for regulating these pathways. We also found that the IMD and Toll pathway regulate AMP expression by cross-talking. The levels of PGRP-LC and Toll mRNAs were upregulated upon Sps1 knockdown (6.4±0.36 and 3.2±0.45-fold, respectively, n=3). Overexpression of each protein also upregulated AMPs. Interestingly, PGRP-LC overexpression upregulated AMP more than Toll overexpression. These data strongly suggest that SPS1 controls the innate immune system of D. melanogaster through regulating PGRP-LC and Toll expression.

Lung surfactant protein D (SP-D) and Dendritic cell-specific intercellular adhesion molecules-3 grabbing non-integrin (DC-SIGN) are pathogen recognising C-type lectin receptors. SP-D has a crucial immune function in detecting and clearing pulmonary pathogens; DC-SIGN is involved in facilitating dendritic cell interaction with naïve T cells to mount an anti-viral immune response. SP-D and DC-SIGN have been shown to interact with various viruses, including SARS-CoV-2, an enveloped RNA virus that causes COVID-19. A recombinant fragment of human SP-D (rfhSP-D) comprising of α-helical neck region, carbohydrate recognition domain, and eight N-terminal Gly-X-Y repeats has been shown to bind SARS-CoV-2 Spike protein and inhibit SARS-CoV-2 replication by preventing viral entry in Vero cells and HEK293T cells expressing ACE2. DC-SIGN has also been shown to act as a cell surface receptor for SARS-CoV-2 independent of ACE2. Since rfhSP-D is known to interact with SARS-CoV-2 Spike protein and DC-SIGN, this study was aimed at investigating the potential of rfhSP-D in modulating SARS-CoV-2 infection. Coincubation of rfhSP-D with Spike protein improved the Spike Protein: DC-SIGN interaction. Molecular dynamic studies revealed that rfhSP-D stabilised the interaction between DC-SIGN and Spike protein. Cell binding analysis with DC-SIGN expressing HEK 293T and THP- 1 cells and rfhSP-D treated SARS-CoV-2 Spike pseudotypes confirmed the increased binding. Furthermore, infection assays using the pseudotypes revealed their increased uptake by DC-SIGN expressing cells. The immunomodulatory effect of rfhSP-D on the DC-SIGN: Spike protein interaction on DC-SIGN expressing epithelial and macrophage-like cell lines was also assessed by measuring the mRNA expression of cytokines and chemokines. RT-qPCR analysis showed that rfhSP-D treatment downregulated the mRNA expression levels of pro-inflammatory cytokines and chemokines such as TNF-α, IFN-α, IL-1β, IL- 6, IL-8, and RANTES (as well as NF-κB) in DC-SIGN expressing cells challenged by Spike protein. Furthermore, rfhSP-D treatment was found to downregulate the mRNA levels of MHC class II in DC expressing THP-1 when compared to the untreated controls. We conclude that rfhSP-D helps stabilise the interaction between SARS- CoV-2 Spike protein and DC-SIGN and increases viral uptake by macrophages via DC-SIGN, suggesting an additional role for rfhSP-D in SARS-CoV-2 infection.

The healthy liver requires a strictly controlled crosstalk between immune and nonimmune cells to maintain its function and homeostasis. A well-conditioned immune system can effectively recognize and clear noxious stimuli by a self-limited, small-scale inflammatory response. This regulated inflammatory process enables the liver to cope with daily microbial exposure and metabolic stress, which is beneficial for hepatic self-renewal and tissue remodeling. However, the failure to clear noxious stimuli or dysregulation of immune response can lead to uncontrolled liver inflammation, liver dysfunction, and severe liver disease. Numerous highly dynamic circulating immune cells and sessile resident immune and parenchymal cells interact and communicate with each other in an incredibly complex way to regulate the inflammatory response in both healthy and diseased liver. Intravital imaging is a powerful tool to visualize individual cells in vivo and has been widely used for dissecting the behavior and interactions between various cell types in the complex architecture of the liver. Here, we summarize some new findings obtained with the use of intravital imaging, which enhances our understanding of the complexity of immune cell behavior, cell–cell interaction, and spatial organization during the physiological and pathological liver inflammatory response.

The NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18. NLRP3 is the most extensively studied inflammasome to date due to its array of activators and aberrant activation in several inflammatory diseases. Studies using small molecules and biologics targeting the NLRP3 inflammasome pathway have shown positive outcomes in treating various disease pathologies by blocking chronic inflammation. In this review, we discuss the recent advances in understanding the NLRP3 mechanism, its role in disease pathology, and provide a broad review of therapeutics discovered to target the NLRP3 pathway and their challenges.

Abstract Background Immune ageing is a result of repetitive microbial challenges along with cell intrinsic or systemic changes occurring during ageing. Mice under ‘specific-pathogen-free’ (SPF) conditions are frequently used to assess immune ageing in long-term experiments. However, physiological pathogenic challenges are reduced in SPF mice. The question arises to what extent murine experiments performed under SPF conditions are suited to analyze immune ageing in mice and serve as models for human immune ageing. Our previous comparisons of same aged mice with different microbial exposures, unambiguously identified distinct clusters of immune cells characteristic for numerous previous pathogen encounters in particular in pet shop mice. Results We here performed single cell mass cytometry assessing splenic as secondary and bone marrow as primary lymphoid organ-derived leukocytes isolated from young versus aged SPF mice in order to delineate alterations of the murine hematopoietic system induced during ageing. We then compared immune clusters from young and aged SPF mice to pet shop mice in order to delineate alterations of the murine hematopoietic system induced by physiological pathogenic challenges and those caused by cell intrinsic or systemic changes during ageing. Notably, distinct immune signatures were similarly altered in both pet shop and aged SPF mice in comparison to young SPF mice, including increased frequencies of memory T lymphocytes, effector-cytokine producing T cells, plasma cells and mature NK cells. However, elevated frequencies of CD4+ T cells, total NK cells, granulocytes, pDCs, cDCs and decreased frequencies of naïve B cells were specifically identified only in pet shop mice. In aged SPF mice specifically the frequencies of splenic IgM+ plasma cells, CD8+ T cells and CD4+ CD25+ Treg were increased as compared to pet shop mice and young mice. Conclusions Our study dissects firstly how ageing impacts both innate and adaptive immune cells in primary and secondary lymphoid organs. Secondly, it partly distinguishes murine intrinsic immune ageing alterations from those induced by physiological pathogen challenges highlighting the importance of designing mouse models for their use in preclinical research including vaccines and immunotherapies.

Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the general population. This disease is characterized by persistent articular inflammation and joint damage driven by the proliferating synovial tissue fibroblasts as well as neutrophil, monocyte and lymphocyte trafficking into the synovium. The factors leading to RA pathogenesis remain poorly elucidated although genetic and environmental factors have been proposed to be the main contributors to RA. The majority of the early studies focused on the role of lymphocytes and adaptive immune responses in RA. However, in the past two decades, emerging studies showed that the innate immune system plays a critical role in the onset and progression of RA pathogenesis. Various innate immune cells including monocytes, macrophages and dendritic cells are involved in inflammatory responses seen in RA patients as well as in driving the activation of the adaptive immune system, which plays a major role in the later stages of the disease. Here we focus the discussion on the role of different innate immune cells and components in initiation and progression of RA. New therapeutic approaches targeting different inflammatory pathways and innate immune cells will be highlighted here. Recent emergence and the significant roles of innate lymphoid cells and inflammasomes will be also discussed.

This study aims to assess the effects of different dietary n-6/n-3 long-chain polyunsaturated fatty acid ratios and CHO content in the immune response of gilthead seabream. For that purpose, gilthead sea bream juveniles (initial body weight = 47.5 g) were fed for 84 days with four isoproteic (47% crude protein) and isolipidic (18% crude lipids) diets with high (20%) or low (5%) level of gelatinized starch (HS or LS diets, respectively) and included approximately 2.4% ARA or DHA. At the end of the trial, the DHA-enriched groups presented increased red blood cell (RBC) count, hemoglobin, plasmatic nitric oxide (NO) content, and antiprotease and alternative complement activities. The ARA groups had increased thrombocyte count, and plasmatic bactericidal activity against Vibrio anguillarum was lower in the fish fed the ARA/LS diet. After the feeding trial, the fish were challenged with an intraperitoneal injection (i.p.) of killed Photobacterium damselae subsp. piscicida (Phdp) and sampled at 4 and 24 h after the challenge. At 4 h after i.p., the ARA groups presented increased plasma total immunoglobulins (Ig) and bactericidal activity against V. anguillarum. In addition, the fish fed the ARA/LS diet presented lower white blood cell (WBC) and alternative complement activity. At 24 h after i.p., the ARA groups presented increased RBC, WBC, and thrombocyte numbers, total IG, plasma peroxidase activity, and casp3 expression in the distal intestine. The HS groups presented increased plasma NO content and bactericidal activity against Phdp and decreased protease, antiprotease activity, and bactericidal activity against V. anguillarum. In conclusion, high dietary DHA levels seemed to improve the immune status of unchallenged gilthead sea bream juveniles, while high dietary ARA levels improved the fish immune response to a bacterial challenge. The energy provided by dietary starch seems to be important to promote a fast response by the fish immune system after a challenge.

An understanding of neuroimmune signaling has become central to a description of how alcohol causes addiction and how it damages people with an AUD. It is well known that the neuroimmune system influences neural activity via changes in gene expression. This review discusses the roles played by CNS Toll-like receptor (TLR) signaling in the response to alcohol. Also discussed are observations in Drosophila that show how TLR signaling pathways can be co-opted by the nervous system and potentially shape behavior to a far greater extent and in ways different than generally recognized. For example, in Drosophila, TLRs substitute for neurotrophin receptors and an NF-κB at the end of a TLR pathway influences alcohol responsivity by acting non-genomically.

Tobacco smoking is a major cause of chronic obstructive pulmonary disease (COPD) and atherosclerotic cardiovascular disease (ASCVD). These diseases share common pathogenesis and significantly influence each other’s clinical presentation and prognosis. There is increasing evidence that the mechanisms underlying the comorbidity of COPD and ASCVD are complex and multifactorial. Smoking-induced systemic inflammation, impaired endothelial function and oxidative stress may contribute to the development and progression of both diseases. The components present in tobacco smoke can have adverse effects on various cellular functions, including macrophages and endothelial cells. Smoking may also affect the innate immune system, impair apoptosis, and promote oxidative stress in the respiratory and vascular systems. The purpose of this review is to discuss the importance of smoking in the mechanisms underlying the comorbid course of COPD and ASCVD.

• IBD was an inflammatory condition of the GI and clinically associated with UC and CD. • Loss of immune tolerance to intestinal antigens leads to intestinal barrier dysfunction in IBD. • Th22 lymphocytes were promoted intestinal epithelial cells' homeostasis by secreting IL-22 in normal state. • The role of Th22 cells in IBD was like a double-edged sword: protective and destructive. The two primary forms of inflammatory disorders of the small intestine and colon that make up inflammatory bowel disease (IBD) are ulcerative colitis (UC) and Crohn's disease (CD). While ulcerative colitis primarily affects the colon and the rectum, CD affects the small and large intestines, as well as the esophagus, mouth, anus, and stomach. Although the etiology of IBD is not completely clear, and there are many unknowns about it, the development, progression, and recurrence of IBD are significantly influenced by the activity of immune system cells, particularly lymphocytes, given that the disease is primarily caused by the immune system stimulation and activation against gastrointestinal (GI) tract components due to the inflammation caused by environmental factors such as viral or bacterial infections, etc. in genetically predisposed individuals. Maintaining homeostasis and the integrity of the mucosal barrier are critical in stopping the development of IBD. Specific immune system cells and the quantity of secretory mucus and microbiome are vital in maintaining this stability. Th22 cells are helper T lymphocyte subtypes that are particularly important for maintaining the integrity and equilibrium of the mucosal barrier. This review discusses the most recent research on these cells' biology, function, and evolution and their involvement in IBD. [ABSTRACT FROM AUTHOR]

Psoriasis is an immune-mediated genetic skin disease. The underlying pathomechanisms involve complex interaction between the innate and adaptive immune system. T-cells interact with dendritic cells, macrophages, and keratinocytes, which can be mediated by their secreted cytokines. Dysregulation of the immune response is thought to result in a chronic imbalance in the production of pro-inflammatory and anti-inflammatory cytokines. Phosphodiesterase (PDE4) act as proinflammatory enzymes via degradation of cAMP, whereas PDE4 inhibitors play an anti- inflammatory role in vitro and in vivo. In particular, topical and systemic PDE4 inhibitor has been approved for the treatment of psoriasis and psoriatic arthritis. However, little is known on the expression pattern of PDE4 in psoriasis. We report that serum PDE4 are overexpressed in blood of patients with chronic plaque psoriasis, as compared with normal controls. PDE4 expression is up-regulated in psoriatic dermis as compared with normal skin, with particular regard to dermal lymphocytes. Taken together, these results indicate that PDE4 play an important role in psoriasis pathogenesis and supports promises put on topical PDE4 inhibitors in treatment of psoriasis. [ABSTRACT FROM AUTHOR]

Canine myxomatous mitral valve disease (MMVD) is similar to Barlow’s form of MMVD in humans. These valvulopathies are complex, with varying speeds of progression. We hypothesized that the relative abundances of serum proteins would help identify the consecutive MMVD stages and discover new disease pathways on a systemic level. To identify distinction-contributing protein panels for disease onset and progression, we compared the proteomic profiles of serum from healthy dogs and dogs with different stages of naturally occurring MMVD. Dogs were divided into experimental groups on the basis of the left-atrium-to-aorta ratio and normalized left ventricular internal dimension in diastole values. Serum was collected from healthy (N = 12) dogs, dogs diagnosed with MMVD in stages B1 (N = 13) and B2 (N = 12) (asymptomatic), and dogs diagnosed with MMVD in chronic stage C (N = 13) (symptomatic). Serum biochemistry and selected ELISAs (galectin-3, suppression of tumorigenicity, and asymmetric dimethylarginine) were performed. Liquid chromatography–mass spectrometry (LC–MS), tandem mass tag (TMT) quantitative proteomics, and statistical and bioinformatics analysis were employed. Most of the 21 serum proteins with significantly different abundances between experimental groups (p < 0.05, FDR ˂ 0.05) were classified as matrix metalloproteinases, protease inhibitors, scaffold/adaptor proteins, complement components, anticoagulants, cytokine, and chaperone. LC–MS TMT proteomics results obtained for haptoglobin, clusterin, and peptidase D were further validated analytically. Canine MMVD stages, including, for the first time, asymptomatic B1 and B2 stages, were successfully distinguished in dogs with the disease and healthy dogs on the basis of the relative abundances of a panel of specific serum proteins. Most proteins with significantly different abundances were involved in immune and inflammatory pathways. Their role in structural remodeling and progression of canine MMVD must be further investigated. Further research is needed to confirm the resemblance/difference with human MMVD. Proteomics data are available via ProteomeXchange with the unique dataset identifier PXD038475.

SARS-CoV-2 severity predictions are feasible, though individual susceptibility is not. The latter prediction allows for planning vaccination strategies and the quarantine of vulnerable targets. Ironically, the innate immune response (InImS) is both an antiviral defense and the potential cause of adverse immune outcomes. The competition for iron has been recognized between both the immune system and invading pathogens and expressed in a ratio of ferritin divided by p87 (as defined by the Adnab-9 ELISA stool-binding optical density, minus the background), known as the FERAD ratio. Associations with the FERAD ratio may allow predictive modeling for the susceptibility and severity of disease. We evaluated other potential COVID-19 biomarkers prospectively. Patients with PCR+ COVID-19 tests (Group 1; n = 28) were compared to three other groups. In Group 2 (n = 36), and 13 patients displayed COVID-19-like symptoms but had negative PCR or negative antibody tests. Group 3 (n = 90) had no symptoms and were negative when routinely PCR-tested before medical procedures. Group 4 (n = 2129) comprised a pool of patients who had stool tests and symptoms, but their COVID-19 diagnoses were unknown; therefore, they were chosen to represent the general population. Twenty percent of the Group 4 patients (n = 432) had sufficient data to calculate their FERAD ratios, which were inversely correlated with the risk of COVID-19 in the future. In a case report of a neonate, we studied three biomarkers implicated in COVID-19, including p87, Src (cellular-p60-sarcoma antigen), and Abl (ABL-proto-oncogene 2). The InImS of the first two were positively correlated. An inverse correlation was found between ferritin and lysozyme in serum (p < 0.05), suggesting that iron could have impaired an important innate immune system anti-viral effector and could partially explain future COVID-19 susceptibility.

The dynamic immunological changes occurring throughout pregnancy are well-orchestrated and important for the success of the pregnancy. One of the key immune adaptations is the maternal immune tolerance towards the semi-allogeneic fetus. In this review, we provide a comprehensive overview of what is known about the innate and adaptive immunological changes in pregnancy and the role(s) of specific immune cells during physiological and pathological pregnancy. Alongside this, we provided details of remaining questions and challenges, as well as future perspectives for this growing field of research. Understanding the immunological changes that occur can inform potential strategies on treatments for the optimal health of the neonate and pregnant individual both during and after pregnancy.

Invertebrates, including crustaceans, rely on cellular and humoral immune responses to protect against extrinsic and intrinsic factors that threaten their integrity. Recently, different immune parameters have been increasingly used as biomarkers of effects of pollutants and environmental change. Here, we describe the dynamics of the innate immune response of the terrestrial crustacean Porcellio scaber to injection of a single dose of lipopolysaccharide (LPS), an important molecular surface component of the outer membrane of Gram-negative bacteria. The aim was to provide a basis for interpretation of change in immune parameters as a result of different challenges, including microplastics and nanoplastics exposure. Changes in total and differential numbers of hemocytes, hemocyte viability, and humoral immune parameters (i.e., phenoloxidase-like activity, nitric oxide levels) were assessed at different times (3, 6, 12, 24, 48 h). An injection of 0.5 μg/μL LPS into the body of P. scaber resulted in a rapid decrease (3 h after LPS injection) in the total number of hemocytes and reduced viability of the hemocytes. This was accompanied by changed proportions of the different hemocyte types, as a decrease in the numbers of semigranulocytes and granulocytes, and a marked increase in the numbers of hyalinocytes. In addition, phenoloxidase-like activity and nitric oxide levels in the hemolymph were increased at 3 h and 6 h, respectively, after the LPS challenge. Forty-eight hours after LPS injection, the immune parameters in the hemolymph of P. scaber had returned to those before the LPS challenge. This suggests that the innate immune system successfully protected P. scaber from the deleterious effects of the LPS challenge. These data indicate the need to consider the dynamics of innate immune responses of P. scaber when effects of infections, pollutants, or environmental changes are studied. We also propose an approach to test the immunocompetence of organisms after different challenges in ecotoxicity studies, based on the dynamics of their immune responses. [ABSTRACT FROM AUTHOR]

Venoms are products of specialized glands and serve many living organisms to immobilize and kill prey, start digestive processes and act as a defense mechanism. Venoms affect different cells, cellular structures and tissues, such as skin, nervous, hematological, digestive, excretory and immune systems, as well as the heart, among other structures. Components of both the innate and adaptive immune systems can be stimulated or suppressed. Studying the effects on the cells and molecules produced by the immune system has been useful in many biomedical fields. The effects of venoms can be the basis for research and development of therapeutic protocols useful in the modulation of the immunological system, including different autoimmune diseases. This review focuses on the understanding of biological effects of diverse venom on the human immune system and how some of their components can be useful for the study and development of immunomodulatory drugs. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a widespread socially significant disease. The development of COPD involves the innate immune system. Interestingly, the regulation of the innate lung immune system is related to the gut microbiota. This connection is due to the production by gut microorganisms of short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. Nutritional disturbances and changes in the structure of the intestinal microbiota lead to a decrease in SCFAs production and their effect on pulmonary immunity. The presence of a metabolic and immune axis linking the lungs and gut plays an important role in the pathogenesis of COPD. In addition, the nature of nutrition and SCFAs may participate in the development of the clinically heterogeneous course of COPD. [ABSTRACT FROM AUTHOR]

The ultimate cause of Alzheimer's disease (AD) is still unknown and no disease-modifying treatment exists. Emerging evidence supports the concept that the immune system has a key role in AD pathogenesis. This awareness leads to the idea that specific parts of the immune system must be engaged to ward off the disease. Immunotherapy has dramatically improved the management of several previously untreatable cancers and could hold similar promise as a novel therapy for treating AD. However, before potent immunotherapies can be rationally designed as treatment against AD, we need to fully understand the dynamic interplay between AD and the different parts of our immune system. Accordingly, here we review the most important aspects of both the innate and adaptive immune system in relation to AD pathology. [ABSTRACT FROM AUTHOR]

The study of immune system aging is of relevance, considering its myriad of interactions and role in protecting and maintaining body homeostasis. While mouse models have been extensively used to study immune system aging, little is known on how the main immune populations progress over time and what is the impact of sex. To contribute to filling this gap, male and female BALB/cByJ mice were longitudinally evaluated, from 3 to 18 months old, for the main blood populations, assessed by flow cytometry. Using linear mixed-effect models, we observed that the percentages of neutrophils, monocytes, eosinophils, and total natural killer (NK) cells increase with aging, while those of B cells, T cells (including CD4+ and CD8+ subsets), and Ly6C+ NK cells decrease. Males present higher percentages of neutrophils and classical monocytes Ly6Chigh over time, while females present higher percentages of total T cells, both CD4+ and CD8+, eosinophils, and NK cells. Males and females display similar percentages of B cells, even though with opposite accelerated progressions over time. This study revealed that mouse models recapitulate what is observed in humans during aging: an overall proportional decrease in the adaptive and an increase in the innate immune cells. Additionally, it uncovers an age-related sexual dimorphism in the proportion of immune cells in circulation, further strengthening the need to explore the impact of sex when addressing immune system aging using mouse models. [ABSTRACT FROM AUTHOR]

A group of nucleic acids and oligonucleotides play various roles in the innate immune system. They can stimulate pattern recognition receptors to activate innate immune cells, encode immunostimulatory proteins or peptides, or silence specific genes to block negative regulators of immune cells. Given the limitations of current cancer immunotherapy, there has been increasing interest in harnessing innate immune responses by nucleic acids and oligonucleotides. The poor biopharmaceutical properties of nucleic acids and oligonucleotides make it critical to use carriers that can protect them in circulation, retain them in the tumor microenvironment, and bring them to intracellular targets. Therefore, various gene carriers have been repurposed to deliver nucleic acids and oligonucleotides for cancer immunotherapy and improve their safety and activity. Here, we review recent studies that employed carriers to enhance the functions of nucleic acids and oligonucleotides and overall immune responses to cancer, and discuss remaining challenges and future opportunities in the development of nucleic acid-based immunotherapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an ever more common neurodegenerative disease among the elderly, characterized by recurrent neuroinflammation and amyloid beta (Aβ) accumulation in the brain parenchyma. Recent genome-wide association studies (GWAS) have shown a distinct role for the innate immune system in AD, with microglia playing a key role. The function of microglial cells is stringently regulated by the neighboring microenvironment in the brain. Upon interruption in diseases, like AD, it demonstrates neurotoxic and neuroprotective action by M1 (neurotoxic) and M2 (neuroprotective) microglial phenotypes, respectively, in the brain. Microglial cells on activation by complement factors, toll-like receptors, and genetic variants result in Aβ' phagocytosis, synaptic pruning, and reactivation of complement pathway. Recent studies have demonstrated the presence of potential therapeutic targets in microglial cells. Immune receptors revealed on microglia as potential drug targets can be paired immunoglobulin-like type 2 receptor (PILR), CD3358, and triggering receptor expressed on myeloid cells 2 (TREM2), as they can have impact on late-onset AD occurrence and progression. Thus, targeting these receptors can accentuate the beneficial effects of microglial cells required to decelerate the progression of AD. This review emphasizes the microglial phenotypes, its function in AD brain, and potential immunological and therapeutic targets to fight this highly progressive neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

NF-κB proteins are well known as transcription factors important in immune system activation. In this highly conserved role, they contribute to changes in behavior in response to infection and in response to a variety of other insults and experiences. In some mammalian neurons, NF-κBs can be found at the synapse and translocate to the nucleus to alter gene expression when activated by synaptic activity. Here, we demonstrate that, in Drosophila melanogaster, NF-κB action is important both inside and outside the nucleus and that the Dif gene has segregated nuclear and non-nuclear NF-κB action into different protein isoforms. The DifA isoform is a canonical nuclear-acting NF-κB protein that enters the nucleus and is important for combating infection. The DifB variant, but not the DifA variant, is found in the central nervous system (mushroom bodies and antennal lobes). DifB does not enter the nucleus and co-localizes with a synaptic protein. In males and females, a DifB mutant alters alcohol behavioral sensitivity without an obvious effect on combating infection, whereas a DifA mutant does not affect alcohol sensitivity but compromises the immune response. These data are evidence that the non-nuclear DifB variant contributes to alcohol behavioral sensitivity by a nongenomic mechanism that diverges from the NF-κB transcriptional effects used in the peripheral immune system. Enrichment of DifB in brain regions rich in synapses and biochemical enrichment of DifB in the synaptoneurosome fraction indicates that the protein may act locally at the synapse. [ABSTRACT FROM AUTHOR]

Visual information is transmitted from the eye to the brain along the optic nerve, a structure composed of retinal ganglion cell (RGC) axons. The optic nerve is highly vulnerable to damage in neurodegenerative diseases, such as glaucoma, and there are currently no FDA-approved drugs or therapies to protect RGCs from death. Zebrafish possess remarkable neuroprotective and regenerative abilities. Here, utilizing an optic nerve transection (ONT) injury and an RNA-seq-based approach, we identify genes and pathways active in RGCs that may modulate their survival. Through pharmacological perturbation, we demonstrate that Jak/Stat pathway activity is required for RGC survival after ONT. Furthermore, we show that immune responses directly contribute to RGC death after ONT; macrophages/microglia are recruited to the retina and blocking neuroinflammation or depleting these cells after ONT rescues survival of RGCs. Taken together, these data support a model in which crosstalk between macrophages/microglia and RGCs, mediated by Jak/Stat pathway activity, regulates RGC survival after optic nerve injury. [ABSTRACT FROM AUTHOR]

Vaccines have demonstrated protection against the morbidity and mortality of COVID-19, but concerns regarding the rare side effect of acute myocarditis have stymied immunization efforts. This review aims to describe the incidence and theorized mechanisms of COVID vaccine-associated myocarditis and review relevant principles for management of vaccine-associated myocarditis Epidemiologic studies of myocarditis after COVID vaccination are reviewed, which show an incidence of approximately 20–30 per million patients. The vast majority of these cases are seen with mRNA vaccines especially in male patients under 30 years of age. Mechanisms are largely theoretical, but molecular mimicry and dysregulated innate immune reactions have been proposed. While studies suggest that this subtype of myocarditis is mild and self-limited, long-term evidence is lacking. Principles of myocarditis treatment and surveillance are outlined as they apply to COVID vaccine-associated myocarditis. COVID vaccine-associated myocarditis is rare but well described in certain at-risk groups. Better understanding of its pathogenesis is key to mitigating this complication and advancing vaccination efforts. Risk-benefit analyses demonstrate that individual- and population-level benefits of vaccination exceed the risks of this rare and mild form of myocarditis. [ABSTRACT FROM AUTHOR]

• Aging affects the ability of human immune system to fight infections and neoplasms. • All components of the innate and adaptive immune system are affected. • Major mechanisms of immune system aging are immunosenescence and inflammaging. • Immunosenescence and inflammaging lead to aging-related chronic inflammatory diseases. • Immunosenescence and inflammaging decide about severity of COVID-19. The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19. [ABSTRACT FROM AUTHOR]

(1) Background: Sepsis is a life-threatening condition caused by an abnormal host response to infection that produces altered physiological responses causing tissue damage and can result in organ dysfunction and, in some cases, death. Although sepsis is characterized by a malfunction of the immune system leading to an altered immune response and immunosuppression, the high complexity of the pathophysiology of sepsis requires further investigation to characterize the immune response in sepsis and septic shock. (2) Methods: This study analyzes the immune-related responses occurring during the early stages of sepsis by comparing the amounts of cytokines, immune modulators and other endothelial mediators of a control group and three types of severe patients: critically ill non-septic patients, septic and septic shock patients. (3) Results: We showed that in the early stages of sepsis the innate immune system attempts to counteract infection, probably via neutrophils. Conversely, the adaptive immune system is not yet fully activated, either in septic or in septic shock patients. In addition, immunosuppressive responses and pro-coagulation signals are active in patients with septic shock. (4) Conclusions: The highest levels of IL-6 and pyroptosis-related cytokines (IL-18 and IL-1α) were found in septic shock patients, which correlated with D-dimer. Moreover, endothelial function may be affected as shown by the overexpression of adhesion molecules such as s-ICAM1 and E-Selectin during septic shock. [ABSTRACT FROM AUTHOR]

Abstract Background Apoptosis is an important process for an organism’s innate immune system to respond to pathogens, while also allowing for cell differentiation and other essential life functions. Caspases are one of the key protease enzymes involved in the apoptotic process, however there is currently a very limited understanding of bivalve caspase diversity and function. Results In this work, we investigated the presence of caspase homologues using a combination of bioinformatics and phylogenetic analyses. We blasted the Crassostrea gigas genome for caspase homologues and identified 35 potential homologues in the addition to the already cloned 23 bivalve caspases. As such, we present information about the phylogenetic relationship of all identified bivalve caspases in relation to their homology to well-established vertebrate and invertebrate caspases. Our results reveal unexpected novelty and complexity in the bivalve caspase family. Notably, we were unable to identify direct homologues to the initiator caspase-9, a key-caspase in the vertebrate apoptotic pathway, inflammatory caspases (caspase-1, − 4 or − 5) or executioner caspases-3, − 6, − 7. We also explored the fact that bivalves appear to possess several unique homologues to the initiator caspase groups − 2 and − 8. Large expansions of caspase-3 like homologues (caspase-3A-C), caspase-3/7 group and caspase-3/7-like homologues were also identified, suggesting unusual roles of caspases with direct implications for our understanding of immune response in relation to common bivalve diseases. Furthermore, we assessed the gene expression of two initiator (Cg2A, Cg8B) and four executioner caspases (Cg3A, Cg3B, Cg3C, Cg3/7) in C. gigas late-larval development and during metamorphosis, indicating that caspase expression varies across the different developmental stages. Conclusion Our analysis provides the first overview of caspases across different bivalve species with essential new insights into caspase diversity, knowledge that can be used for further investigations into immune response to pathogens or regulation of developmental processes.

The contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases is an outstanding question. Sustained activation of the peripheral innate and adaptive immune systems occurs in the context of a broad array of disorders ranging from chronic infectious diseases to autoimmune and metabolic diseases. In addition, progressive systemic inflammation is increasingly recognized during aging. Peripheral immune cells could potentially modulate the cellular brain environment via the secretion of soluble molecules. There is an ongoing debate whether peripheral immune cells have the potential to migrate into the brain under certain permissive circumstances. In this perspective, we discuss the possible contribution of chronic peripheral inflammation to the pathogenesis of age-related neurodegenerative diseases with a focus on microglia, the resident immune cells of the brain parenchyma.

Bushra Mdkhana,1 Narjes Saheb Sharif-Askari,1 Rakhee K Ramakrishnan,1 Swati Goel,1 Qutayba Hamid,1– 3 Rabih Halwani1,2 1Sharjah Institute of Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 2Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; 3Meakins-Christie Laboratories, Research Institute of the McGill University Health Center, Montreal, Quebec, CanadaCorrespondence: Rabih HalwaniCollege of Medicine, University of Sharjah, Sharjah, United Arab EmiratesEmail rhalwani@sharjah.ac.aeAbstract: The coronavirus disease 2019 (COVID-19) pandemic has affected millions of people and crippled economies worldwide. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for this pandemic has triggered avid research on its pathobiology to better understand the pathophysiology of COVID-19. In the absence of approved antiviral therapeutic strategies or vaccine platforms capable of effectively targeting this global threat, the hunt for effective therapeutics has led to many candidates being actively evaluated for their efficacy in controlling or preventing COVID-19. In this review, we gathered current evidence on the innate nucleic acid-sensing pathways expected to be elicited by SARS-CoV-2 and the immune evasion mechanisms they have developed to promote viral replication and infection. Within the nucleic acid-sensing pathways, SARS-CoV-2 infection and evasion mechanisms trigger the activation of NOD-signaling and NLRP3 pathways leading to the production of inflammatory cytokines, IL-1β and IL-6, while muting or blocking cGAS-STING and interferon type I and III pathways, resulting in decreased production of antiviral interferons and delayed innate response. Therefore, blocking the inflammatory arm and boosting the interferon production arm of nucleic acid-sensing pathways could facilitate early control of viral replication and dissemination, prevent disease progression, and cytokine storm development. We also discuss the rationale behind therapeutic modalities targeting these sensing pathways and their implications in the treatment of COVID-19.Keywords: COVID-19, SARS-CoV-2, innate immune system, nucleic acid sensing, immune evasion, NLRP3, cGAS-STING, coronavirus

This review of the scientific literature deals with the participation of αβT and γδT cells of the innate immune system in maintaining an anti-inflammatory environment in the physiological state of adipose tissue and their role in the development of meta-inflammation in obesity. Overweight due to an increase in adipose tissue is associated with the development of metabolic disorders, which not only significantly reduce the quality of life, but also have the risk of adverse cardiovascular events. According to modern concepts, the trigger of metabolic disorders is low-grade inflammation induced by adipocyte dysfunction in obesity. Metabolically active cells such as adipocytes in obesity secrete numerous anti-inflammatory cytokines and chemokines, which recruit various immune cells into adipose tissue or activate cells of the immune system, including T cells of the innate immune system. In obesity, mucosal-associated invariant T (MAIT) cells of adipose tissue express an overactivated phenotype and are characterized by unresponsiveness to signals of the TCR-associated pathway, significantly increasing in obese children than in children with physiological body weight. The data are presented on the importance of invariant natural killer T (iNKT) cells, which critically administer the functioning of Treg cells and macrophages in adipose tissue, activation of which causes not only the death of adipocytes, but also stimulates adipogenesis that promotes insulin-dependent glucose uptake by adipocytes, and, in turn, a decrease in the number of iNKT cells, which observed in obesity, leads to the development of meta-inflammation. Variable NKT cells excite plasmacytoid dendritic cells and induce a tolerogenic effect on conventional dendritic cells. The data are given that a decrease in the representation of γδT cells in adipose tissue in obesity determines the intensity of meta-inflammation and insulin resistance in experimental animals receiving a high-fat diet. In the near future, drug control of the activity of MAIT, NKT, and γδT cells may become one of the possible ways to suppress the activity of obesity-induced meta-inflammation and prevent the development of metabolic disorders.

Invertebrates, including crustaceans, rely on cellular and humoral immune responses to protect against extrinsic and intrinsic factors that threaten their integrity. Recently, different immune parameters have been increasingly used as biomarkers of effects of pollutants and environmental change. Here, we describe the dynamics of the innate immune response of the terrestrial crustacean Porcellio scaber to injection of a single dose of lipopolysaccharide (LPS), an important molecular surface component of the outer membrane of Gram-negative bacteria. The aim was to provide a basis for interpretation of change in immune parameters as a result of different challenges, including microplastics and nanoplastics exposure. Changes in total and differential numbers of hemocytes, hemocyte viability, and humoral immune parameters (i.e., phenoloxidase-like activity, nitric oxide levels) were assessed at different times (3, 6, 12, 24, 48 h). An injection of 0.5 μg/μL LPS into the body of P. scaber resulted in a rapid decrease (3 h after LPS injection) in the total number of hemocytes and reduced viability of the hemocytes. This was accompanied by changed proportions of the different hemocyte types, as a decrease in the numbers of semigranulocytes and granulocytes, and a marked increase in the numbers of hyalinocytes. In addition, phenoloxidase-like activity and nitric oxide levels in the hemolymph were increased at 3 h and 6 h, respectively, after the LPS challenge. Forty-eight hours after LPS injection, the immune parameters in the hemolymph of P. scaber had returned to those before the LPS challenge. This suggests that the innate immune system successfully protected P. scaber from the deleterious effects of the LPS challenge. These data indicate the need to consider the dynamics of innate immune responses of P. scaber when effects of infections, pollutants, or environmental changes are studied. We also propose an approach to test the immunocompetence of organisms after different challenges in ecotoxicity studies, based on the dynamics of their immune responses.

ABSTRACT: This study aimed to determine whether the innate immune system in the proventriculus of broiler chicks responds to lipopolysaccharide (LPS) and whether this response is affected by Newcastle disease and infectious bronchitis (ND/IB) vaccination. Chicks were divided into 4 groups: nonvaccinated and injected with PBS or LPS (V-L- and V-L+), and vaccinated and injected with PBS or LPS (V+L- and V+L+). Vaccination was performed on d 1, and LPS was intraperitoneally injected on d 11 of age. The gene expression and protein levels of immune molecules, including toll-like receptors (TLRs), antimicrobial peptides, interleukin-1β (IL-1B), and immunoglobulin A (IgA) in the proventriculus and serum were analyzed. The results showed that the expression levels of TLR21 were higher in vaccinated (V+L-) group than in nonvaccinated (V-L-) group. Gene expression levels of avian β-defensin (AvBDs) and cathelicidin1 (Cath1) were not different among the 4 groups. However, the results of LC/MS analysis showed that the levels of AvBD2, 6, and 7 significantly increased after the LPS challenge in nonvaccinated and vaccinated chicks; the levels were higher in V-L+ and V+L+ than in V-L- and V+L-, respectively. Immunohistochemistry analysis revealed the localization of AvBD1 protein in the epithelial cells of the surface glands and AvBD2 and CATH1 in the heterophil-like cells in the lamina propria of surface glands. Although IL-1B gene expression and protein concentration in the proventriculus tissues were not different among the 4 groups, serum IL-1B levels were upregulated by LPS in both the nonvaccinated and vaccinated groups (V-L- vs. V-L+, V+L- vs. V+L+). Moreover, IgA levels in the proventriculus and serum were not affected by vaccination or LPS challenge. Taken together, we conclude that LPS derived from gram-negative bacteria upregulates the innate immune system, including antimicrobial peptide synthesis in the proventriculus. ND/IB vaccination may not significantly affect antimicrobial peptide synthesis in response to LPS; however, TLR21 expression is upregulated by that vaccination. The antimicrobial peptides synthesized in the proventriculus probably prevent pathogenic microbes from entering the intestine.

Longitudinal studies of various vertebrate populations have demonstrated senescent declines in reproductive performance and survival probability to be almost ubiquitous. Longitudinal studies of potential underlying proximate mechanisms, however, are still scarce.Due to its critical function in the maintenance of health and viability, the immune system is among the potential (mediators of) proximate mechanisms that could underlie senescence.Here, we studied three innate immune parameters—haemagglutination titre, haemolysis titre and haptoglobin concentration—in a population of common terns (Sterna hirundo) known to undergo actuarial senescence. We repeatedly sampled birds of known sex and age across 11 years and used random regression models to (a) quantify how immune parameters vary among individuals and (b) describe within‐individual age‐specific changes in, and potential trade‐offs between, immune parameters.Our models revealed no differences between males and females in haemagglutination titre and haptoglobin concentration, and very low among‐individual variation in these parameters in general. Within individuals, haemagglutination titre increased with age, while haptoglobin concentration did not change. We found no indication for selective (dis)appearance in relation to haemagglutination titre or haptoglobin concentration, nor for the existence of a trade‐off between them. Haemolysis was absent in the majority (76%) of samples.Common terns do not exhibit clear senescence in haemagglutination titre and haptoglobin concentration and show very little among‐individual variation in these parameters in general. This may be explained by canalisation of the immune parameters or by the colonial breeding behaviour of our study species, but more longitudinal studies are needed to facilitate investigation of links between species' characteristics and immunosenescence in wild animals. [ABSTRACT FROM AUTHOR]