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Atherosclerosis is an important medical and social problem, and the keys to solving this problem are still largely unknown. A common situation in real clinical practice is the comorbid course of atherosclerosis with chronic obstructive pulmonary disease (COPD). Diseases share some common risk factors and may be closely linked pathogenetically. Methods: Bioinformatics analysis of datasets from Gene Expression Omnibus (GEO) was performed to examine the gene ontology (GO) of common differentially expressed genes (DEGs) in COPD and peripheral arterial atherosclerosis. DEGs were identified using the limma R package with the settings p < 0.05, corrected using the Benjamini & Hochberg algorithm and ǀlog 2FCǀ > 1.0. The GO, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and the protein–protein interaction (PPI) network analysis were performed with the detected DEGs. Results: The biological processes and signaling pathways involving common DEGs from airway epithelial datasets in COPD and tissue in peripheral atherosclerosis were identified. A total of 15 DEGs were identified, comprising 12 upregulated and 3 downregulated DEGs. The GO enrichment analysis demonstrated that the upregulated hub genes were mainly involved in the inflammatory response, reactive oxygen species metabolic process, cell adhesion, lipid metabolic process, regulation of angiogenesis, icosanoid biosynthetic process, and cellular response to a chemical stimulus. The KEGG pathway enrichment analysis demonstrated that the common pathways were Toll-like receptor signaling pathway, NF-kappa B signaling pathway, lipid and atherosclerosis, and cytokine–cytokine receptor interaction. Conclusions: Biological processes and signaling pathways associated with the immune response may link the development and progression of COPD and atherosclerosis.

Host defense peptides (HDPs) are short cationic peptides that play a key role in the innate immune response of all living organisms. Their action mechanism does not depend on the presence of protein receptors, but on their ability to target and disrupt the membranes of a wide range of pathogenic and pathologic cells which are recognized by their specific compositions, typically with a relatively high concentration of anionic lipids. Lipid profile singularities have been found in cancer, inflammation, bacteria, viral infections, and even in senescent cells, enabling the possibility to use them as therapeutic targets and/or diagnostic biomarkers. Molecular dynamics (MD) simulations are extraordinarily well suited to explore how HDPs interact with membrane models, providing a large amount of qualitative and quantitative information that, nowadays, cannot be assessed by wet-lab methods at the same level of temporal and spatial resolution. Here, we present SuPepMem, an open-access repository containing MD simulations of different natural and artificial peptides with potential membrane lysis activity, interacting with membrane models of healthy mammal, bacteria, viruses, cancer or senescent cells. In addition to a description of the HDPs and the target systems, SuPepMem provides both the input files necessary to run the simulations and also the results of some selected analyses, including structural and MD-based quantitative descriptors. These descriptors are expected to be useful to train machine learning algorithms that could contribute to design new therapeutic peptides. Tools for comparative analysis between different HDPs and model membranes, as well as to restrict the queries to structural and time-averaged properties are also available. SuPepMem is a living project, that will continuously grow with more simulations including peptides of different sequences, MD simulations with different number of peptide units, more membrane models and also several resolution levels. The database is open to MD simulations from other users (after quality check by the SuPepMem team). SuPepMem is freely available under https://supepmem.com/.

Abstract Background Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. Methods NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG5000, which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. Results Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG5000 by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. Conclusions The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy. Graphical Abstract

The eye is a hard-to-treat organ due to its poor regenerative capacity and susceptibility to inflammation; as a result, it has an immune privilege mechanism. In the case of ocular degenerative disorders, chronic and uncontrolled ocular inflammations can overcome this immune response to initiate and exacerbate tissue degeneration, ultimately leading to blindness. Recent landmark discoveries on the key roles of the ocular innate immune system in regulating acute and chronic inflammations as well as tissue fibrosis and homeostasis have shed light on the value of novel treatment interventions in modulating ocular immune responses at the molecular, cellular, and tissue levels. This strategy can be attained by using therapeutics to target resident phagocytes and antigen-presenting cells, namely, microglia and dendritic cells, as well as infiltrating neutrophils and macrophages. Biomaterials are foreign materials to the host and interact with innate immune cells. To leverage such intrinsic immunomodulatory properties, biomaterials such as implants, injectable depots, and nano/micro particles can be used alone as a treatment or with different payloads as carriers in immune-related ocular disorders. This article discusses how physicochemical properties such as biodegradability, size, shape, and charge affect biomaterials’ interaction with the eye’s innate immune system, therefore influencing outcomes towards pro- or anti-inflammatory responses. Knowledge about the eye’s immunological response is required for designing tolerogenic biomaterials including intraocular lenses, cellular scaffolds, therapeutic molecule depots, or carriers of gene therapies. The discussion presented in this review will shed light on the potential use of biomaterials to direct immune responses toward favorable treatment outcomes.

The immune system has evolved to defend organisms against exogenous threats such as viruses, bacteria, fungi, and parasites by distinguishing between “self” and “non-self”. In addition, it guards us against other diseases, such as cancer, by detecting and responding to transformed and senescent cells. However, for survival and propagation, the altered cells and invading pathogens often employ a wide range of mechanisms to avoid, inhibit, or manipulate the immunorecognition. As such, the development of new modes of therapeutic intervention to augment protective and prevent harmful immune responses is desirable. Nucleic acids are biopolymers essential for all forms of life and, therefore, delineating the complex defensive mechanisms developed against non-self nucleic acids can offer an exciting avenue for future biomedicine. Nucleic acid technologies have already established numerous approaches in therapy and biotechnology; recently, rationally designed nucleic acids nanoparticles (NANPs) with regulated physiochemical properties and biological activities has expanded our repertoire of therapeutic options. When compared to conventional therapeutic nucleic acids (TNAs), NANP technologies can be rendered more beneficial for synchronized delivery of multiple TNAs with defined stabilities, immunological profiles, and therapeutic functions. This review highlights several recent advances and possible future directions of TNA and NANP technologies that are under development for controlled immunomodulation.

Cardiovascular (CV) events are increased 36-fold in patients with end-stage renal disease. However, randomized controlled trials to lower LDL cholesterol (LDL-C) and serum total cholesterol (TC) have not shown significant mortality improvements. An inverse association of TC and LDL-C with all-cause and CV mortality has been observed in patients on chronic dialysis. Lipoproteins also may protect against infectious diseases. We used data from 37,250 patients in the international Monitoring Dialysis Outcomes (MONDO) database to evaluate the association between lipids and infection-related or CV mortality. The study began on the first day of lipid measurement and continued for up to 4 years. We applied Cox proportional models with time-varying covariates to study associations of LDL-C, HDL cholesterol (HDL-C), and triglycerides (TGs) with all-cause, CV, infectious, and other causes of death. Overall, 6,147 patients died (19.2% from CV, 13.2% from infection, and 67.6% from other causes). After multivariable adjustment, higher LDL-C, HDL-C, and TGs were independently associated with lower all-cause death risk. Neither LDL-C nor TGs were associated with CV death, and HDL-C was associated with lower CV risk. Higher LDL-C and HDL-C were associated with a lower risk of death from infection or other non-CV causes. LDL-C was associated with reduced all-cause and infectious, but not CV mortality, which resulted in the inverse association with all-cause mortality.

Cyclic GMP–AMP synthase (cGAS), a crucial innate immune sensor, recognizes cytosolic DNA and induces stimulator of interferon genes (STING) to produce type I interferon and other proinflammatory cytokines, thereby mediating innate immune signaling. The cGAS–STING pathway is involved in the regulation of infectious diseases, anti-tumor immunity, and autoimmune diseases; in addition, it plays a key role in the development of central nervous system (CNS) diseases. Therapeutics targeting the modulation of cGAS–STING have promising clinical applications. Here, we summarize the cGAS–STING signaling mechanism and the recent research on its role in CNS diseases.

Ovarian cancer is fatal to women and has a high mortality rate. Although on-going efforts are never stopped in identifying diagnostic and intervention strategies, the disease is so far unable to be well managed. The most important reason for this is the complexity of pathogenesis for OC, and therefore, uncovering the essential molecular biomarkers accompanied with OC progression takes the privilege for OC remission. Inflammation has been reported to participate in the initiation and progression of OC. Both microenvironmental and tumor cell intrinsic inflammatory signals contribute to the malignancy of OC. Inflammation responses can be triggered by various kinds of stimulus, including endogenous damages and exogenous pathogens, which are initially recognized and orchestrated by a series of innate immune system related receptors, especially Toll like receptors, and cyclic GMP-AMP synthase. In this review, we will discuss the roles of innate immune system related receptors, including TLRs and cGAS, and responses both intrinsic and exogenetic in the development and treatment of OC.

BackgroundThe disruption of immune homeostasis after trauma is a major cause of post-traumatic organ dysfunction and/or sepsis. Recently, a variety of neutrophil phenotypes with distinct functions have been identified and suggested as involved in various clinical conditions. The association between neutrophil phenotypes and post-traumatic immunodeficiency has also been reported, yet the specific neutrophil phenotypes and their functional significance in post-traumatic sepsis have not been fully clarified. Therefore, we sought to investigate neutrophil phenotypic changes in a murine model, as these may hold prognostic value in post-traumatic sepsis.Materials and methodsThird-degree burns affecting 25% of the body surface area were used to establish trauma model, and sepsis was induced 24 h later through cecal ligation and puncture (CLP). The Burn/CLP post-traumatic sepsis model and the Sham/CLP control model were established to assess the immunological status after trauma. Histopathological evaluation was performed on the spleen, liver, kidneys, and lung tissues. Immunological evaluation included the assessment of neutrophil markers using mass cytometry as well as cytokine measurements in serum and ascitic fluid through multiplex analysis using LUMINEX®.ResultsThe Burn/CLP group had a lower survival rate than the Sham/CLP group. Histopathological examination revealed an impaired immune response and more advanced organ damage in the Burn/CLP group. Furthermore, the Burn/CLP group exhibited higher levels of transforming growth factor-beta 1 in the blood and generally lower levels of cytokines than the Sham/CLP group. CD11b, which is involved in neutrophil adhesion and migration, was highly expressed on neutrophils in the Burn/CLP group. The expression of CD172a, which is related to the inhibition of phagocytosis, was also upregulated on neutrophils in the Burn/CLP group. The expression of sialic acid-binding lg-like lectin F and CD68 also differed between the two groups.ConclusionDifferent neutrophil phenotypes were observed between Burn/CLP and Sham/CLP groups, suggesting that neutrophils are implicated in the immune imbalance following trauma. However, further studies are needed to prove the causal relationships between neutrophil phenotypes and outcomes, including survival rate and organ dysfunction.

Pyogenic bacteria are associated with a wide range of clinical manifestations, ranging from common and relatively mild respiratory and cutaneous infections to life-threatening localized or systemic infections, such as sepsis and profound abscesses. Despite vaccination and the widespread use of effective antibiotic treatment, severe infection is still observed in a subset of affected patients. We aim to summarize the available data regarding inborn errors of immunity that result in a high risk of severe pyogenic infections. Case series, as well as review and original articles on human genetic susceptibility to pyogenic infections were examined. We review host-associated factors resulting in inborn errors of immunity and leading to a susceptibility to pyogenic infections, including deficiency in major components of the immune system (e.g., neutrophils, complement, immunoglobulin, and spleen function) and novel monogenic disorders resulting in specific susceptibility to pyogenic infection. Specifically, innate immune system deficiency involving toll-like receptors and associated signaling typically predispose to a narrow spectrum of bacterial diseases in otherwise healthy people, making a diagnosis more difficult to suspect and confirm. More complex syndromes, such as hyper IgE syndrome, are associated with a high risk of pyogenic infections due to an impairment of the interleukin-6 or -17 signaling, demonstrating the pivotal role of these pathways in controlling bacterial infections. In clinical practice, awareness of such conditions is essential, especially in the pediatric setting, to avoid a potentially fatal diagnostic delay, set the most proper and prompt treatment, and ensure prevention of severe complications. [ABSTRACT FROM AUTHOR]

While myeloperoxidase (MPO) serves as an indicator of both neutrophil and innate-immune-system function, the potential suppression of the innate immune system in patients with acute myocardial infarction (AMI)-induced depression might be evidenced by a decrease in MPO serum levels. The aim of this prospective study was to (1) determine whether serum concentrations of MPO vary immediately and 6 months after AMI and (2) to investigate whether MPO concentrations at the time of the AMI are significant predictors of AMI-induced depression and the depression-associated suppression of the innate immune system. A total of 109 AMI patients were assessed with the Hamilton Depression Scale (HAMD-17) immediately after admission to the hospital and 6 months later. The MPO status was assessed with serum samples, which were also collected immediately and 6 months after AMI. The depressive patients showed significantly lower MPO blood levels immediately and 6 months after the AMI compared to the patients without depression (ANCOVA: MPO (depression) F = 4.764, df = 1, p = 0.031). The baseline MPO was observed as a significant predictor (p = 0.027) of AMI-induced depression 6 months after AMI. MPO is a potential biomarker for AMI-induced depression, indicating a depression-associated suppression of the innate immune system. [ABSTRACT FROM AUTHOR]

The prevalence of poor metabolic health is growing exponentially worldwide. This condition is associated with complex comorbidities that lead to a compromised quality of life. One of the contributing factors recently gaining attention is exposure to environmental chemicals, such as endocrine-disrupting chemicals (EDCs). Considerable evidence suggests that EDCs can alter the endocrine system through immunomodulation. More concerning, EDC exposure during the fetal development stage has prominent adverse effects later in life, which may pass on to subsequent generations. Although the mechanism of action for this phenomenon is mostly unexplored, recent reports implicate that non-coding RNAs, such as microRNAs (miRs), may play a vital role in this scenario. MiRs are significant contributors in post-transcriptional regulation of gene expression. Studies demonstrating the immunomodulation of EDCs via miRs in metabolic health or towards the Developmental Origins of Health and Disease (DOHaD) Hypothesis are still deficient. The aim of the current review was to focus on studies that demonstrate the impact of EDCs primarily on innate immunity and the potential role of miRs in metabolic health. [ABSTRACT FROM AUTHOR]

Stability constrains evolution. While much is known about constraints on destabilizing mutations, less is known about the constraints on stabilizing mutations. We recently identified a mutation in the innate immune protein S100A9 that provides insight into such constraints. When introduced into human S100A9, M63F simultaneously increases the stability of the protein and disrupts its natural ability to activate Toll-like receptor 4. Using chemical denaturation, we found that M63F stabilizes a calciumbound conformation of hS100A9. We then used NMR to solve the structure of the mutant protein, revealing that the mutation distorts the hydrophobic binding surface of hS100A9, explaining its deleterious effect on function. Hydrogen–deuterium exchange (HDX) experiments revealed stabilization of the region around M63F in the structure, notably Phe37. In the structure of the M63F mutant, the Phe37 and Phe63 sidechains are in contact, plausibly forming an edge-face π-stack. Mutating Phe37 to Leu abolished the stabilizing effect of M63F as probed by both chemical denaturation and HDX. It also restored the biological activity of S100A9 disrupted by M63F. These findings reveal that Phe63 creates a molecular staple with Phe37 that stabilizes a nonfunctional conformation of the protein, thus disrupting function. Using a bioinformatic analysis, we found that S100A9 proteins from different organisms rarely have Phe at both positions 37 and 63, suggesting that avoiding a pathological stabilizing interaction indeed constrains S100A9 evolution. This work highlights an important evolutionary constraint on stabilizing mutations, namely, that they must avoid inappropriately stabilizing nonfunctional protein conformations. [ABSTRACT FROM AUTHOR]

When the organism encounters a foreign substance, it responds with mutual and regular interactions at different stages of the immune system. In airway diseases, the first encounter is at the epithelial level, where innate immune cells and their responses form the first leg of the protective mechanism. The most important barrier for environmental damage is the epithelial barrier. However, the epithelial barrier is not just a mechanical barrier. The formation of the microbiome on the epithelium and the tolerance or intolerance to environmental factors are vital. This vital balance is maintained between the epithelial surface and the subepithelial innate immune system. This is achieved by the epithelial line, which is a mechanical and functional barrier between them. In this respect, epithelial barrier function preservation has an important role in the development and prognosis of airway disease. [ABSTRACT FROM AUTHOR]

Middle ear cholesteatoma (MEC), is a destructive, and locally invasive lesion in the middle ear driven by inflammation with an annual incidence of 10 per 100,000. Surgical extraction/excision remains the only treatment strategy available and recurrence is high (up to 40%), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review was targeted at connecting the dysregulated inflammatory network of MEC to pathogenesis and identification of pharmaceutical targets. We summarized the numerous basic research endeavors undertaken over the last 30+ years to identify the key targets in the dysregulated inflammatory pathways and judged the level of evidence for a given target if it was generated by in vitro, in vivo or clinical experiments. MEC pathogenesis was found to be connected to cytokines characteristic for Th1, Th17 and M1 cells. In addition, we found that the inflammation created damage associated molecular patterns (DAMPs), which further promoted inflammation. Similar positive feedback loops have already been described for other Th1/Th17 driven inflammatory diseases (arthritis, Crohn's disease or multiple sclerosis). A wide-ranging search for molecular targeted therapies (MTT) led to the discovery of over a hundred clinically approved drugs already applied in precision medicine. Based on exclusion criteria designed to enable fast translation as well as efficacy, we condensed the numerous MTTs down to 13 top drugs. The review should serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history. 9oEnHnw4b3NC5oSfFmj_8G Video Abstract Plain English summary: Middle ear cholesteatoma (MEC) is a destructive and locally invasive ulcerated lesion in the middle ear driven by inflammation which occurs in 10 out of 100,000 people annually. Surgical extraction/excision is the only treatment strategy available and recurrence is high (up to 40% after ten years), therefore developing the first pharmaceutical treatments for MEC is desperately required. This review is focused on the connections between inflammation and MEC pathogenesis. These connections can be used as attack points for pharmaceuticals. For this we summarized the results of research undertaken over the last 30 + years. MEC pathogenesis can be described by specific inflammatory dysregulation already known from arthritis, Crohn's disease or multiple sclerosis. A hallmark of this dysregulation are positive feedback loops of the inflammation further amplifying itself in a vicious circle-like manner. We have identified over one hundred drugs which are already used in clinic to treat other inflammatory diseases, and could potentially be repurposed to treat MEC. To improve and expedite clinical success rates, we applied certain criteria based on our literature searches and condensed these drugs down to the 13 top drugs. We hope the review will serve as groundwork for the primary goal, which is to provide potential pharmaceutical therapies to MEC patients for the first time in history. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is a rapidly progressive perinatal inflammatory disease, resulting in liver failure. Hepatic Ly6CLo non-classical monocytes promote the resolution of perinatal liver inflammation during rhesus rotavirus-mediated (RRV) BA in mice. In this study, we aim to investigate the effects of inflammation on the transcription factor Nr4a1, a known regulator of non-classical monocytes. Nr4a1-GFP reporter mice were injected with PBS for control or RRV within 24 h of delivery to induce perinatal liver inflammation. GFP expression on myeloid immune populations in the liver and bone marrow (BM) was quantified 3 and 14 days after injection using flow cytometry. Statistical significance was determined using a student's t-test and ANOVA, with a p-value < 0.05 for significance. Our results demonstrate that non-classical monocytes in the neonatal liver exhibit the highest mean fluorescence intensity (MFI) of Nr4a1 (Ly6CLo MFI 6344 vs. neutrophils 3611 p < 0.001; macrophages 2782; p < 0.001; and Ly6CHi classical monocytes 4485; p < 0.0002). During inflammation, hepatic Ly6CLo non-classical monocytes showed a significant increase in Nr4a1 expression intensity from 6344 to 7600 (p = 0.012), while Nr4a1 expression remained unchanged on the other myeloid populations. These findings highlight the potential of using Nr4a1 as a regulator of neonatal hepatic Ly6CLo non-classical monocytes to mitigate perinatal liver inflammation. [ABSTRACT FROM AUTHOR]

The freshwater snail Biomphalaria glabrata is an intermediate host of Schistosoma mansoni, the agent of human intestinal schistosomiasis. However, much is to be discovered about its innate immune system that appears as a complex black box, in which the immune cells (called hemocytes) play a major role in both cellular and humoral response towards pathogens. Until now, hemocyte classification has been based exclusively on cell morphology and ultrastructural description and depending on the authors considered from 2 to 5 hemocyte populations have been described. In this study, we proposed to evaluate the hemocyte heterogeneity at the transcriptomic level. To accomplish this objective, we used single cell RNA sequencing (scRNAseq) technology coupled to a droplet-based system to separate hemocytes and analyze their transcriptome at a unique cell level in naive Biomphalaria glabrata snails. We were able to demonstrate the presence of 7 hemocyte transcriptomic populations defined by the expression of specific marker genes. As a result, scRNAseq approach showed a high heterogeneity within hemocytes, but provides a detailed description of the different hemocyte transcriptomic populations in B. glabrata supported by distinct cellular functions and lineage trajectory. As a main result, scRNAseq revealed the 3 main population as a super-group of hemocyte diversity but, on the contrary, a great hemocytes plasticity with a probable capacity of hemocytes to engage to different activation pathways. This work opens a new field of research to understand the role of hemocytes particularly in response to pathogens, and towards S. mansoni parasites. [ABSTRACT FROM AUTHOR]

Atherosclerosis is one of the key problems of modern medicine, which is due to the high prevalence of atherosclerotic cardiovascular diseases and their significant share in the structure of morbidity and mortality in many countries. Atherogenesis is a complex chain of events that proceeds over many years in the vascular wall with the participation of various cells. Endothelial cells are key participants in vascular function. They demonstrate involvement in the regulation of vascular hemodynamics, metabolism, and innate immunity, which act as leading links in the pathogenesis of atherosclerosis. These endothelial functions have close connections and deep evolutionary roots, a better understanding of which will improve the prospects of early diagnosis and effective treatment. [ABSTRACT FROM AUTHOR]

In mammalian species, pregnancy is a complex process that involves the maternal recognition of pregnancy, implantation, decidualization, placentation, and parturition. The innate immune system is composed of cellular components, such as natural killer cells, neutrophils, monocytes, and macrophages, and effector molecules, such as cytokines, interferons, antimicrobial peptides, and complement components. The innate immune system plays a critical role as the first line of defense against infection or inflammation to maintain homeostasis and activate the adaptive immunity. During pregnancy, innate immune cells and effector molecules act on the regulation of innate immunity for host defense and processes such as embryo development, implantation, and placentation at the maternal-conceptus interface. In this review, we describe the components of the innate immune system and their functions at the maternal-conceptus interface to establish and maintain pregnancy in animal species that form hemochorial- or epitheliochorial-type placentas, including humans, rodents, ruminants, and pigs.

Neurodegenerative diseases (NDs) are a type of common chronic progressive disorders characterized by progressive damage to specific cell populations in the nervous system, ultimately leading to disability or death. Effective treatments for these diseases are still lacking, due to a limited understanding of their pathogeneses, which involve multiple cellular and molecular pathways. The triggering of an immune response is a common feature in neurodegenerative disorders. A critical challenge is the intricate interplay between neuroinflammation, neurodegeneration, and immune responses, which are not yet fully characterized. In recent years, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway, a crucial immune response for intracellular DNA sensing, has gradually gained attention. However, the specific roles of this pathway within cellular types such as immune cells, glial and neuronal cells, and its contribution to ND pathogenesis, remain not fully elucidated. In this review, we systematically explore how the cGAS-STING signaling links various cell types with related cellular effector pathways under the context of NDs for multifaceted therapeutic directions. We emphasize the discovery of condition-dependent cellular heterogeneity in the cGAS-STING pathway, which is integral for understanding the diverse cellular responses and potential therapeutic targets. Additionally, we review the pathogenic role of cGAS-STING activation in Parkinson's disease, ataxia-telangiectasia, and amyotrophic lateral sclerosis. We focus on the complex bidirectional roles of the cGAS-STING pathway in Alzheimer's disease, Huntington's disease, and multiple sclerosis, revealing their double-edged nature in disease progression. The objective of this review is to elucidate the pivotal role of the cGAS-STING pathway in ND pathogenesis and catalyze new insights for facilitating the development of novel therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Background: Beta-2 microglobulin (β2M) is acknowledged as a prognostic biomarker for B-cell malignancies. However, insights into the impact of β2M on B-cell malignancy risk, and vice versa, are limited., Methods: We conducted a genome-wide meta-analysis (GWMA), bidirectional two-sample Mendelian randomization (TSMR) analysis, and pathway enrichment analysis to explore the causal relationship between β2M and B-cell malignancies and the underlying biological processes., Results: The GWMA identified 55 lead SNPs across five genomic regions (three novel: WDR72, UMOD, and NLRC5) associated with β2M. In the UKB, genetically predicted β2M showed a positive association with diffuse large B-cell lymphoma (DLBCL; odds ratio [OR]: 1.742 per standard deviation increase in β2M; 95% confidence interval [CI]: 1.215-2.498; P = 3.00 × 10 -3 ; FDR = 7.50× 10 -3 ) and Hodgkin lymphoma (HL; OR: 2.270; 95% CI: 1.525-3.380; P = 5.15 × 10 -5 ; FDR =2.58 × 10 -4 ). However, no associations were found with follicular lymphoma (FL), chronic lymphoid leukemia (CLL), or multiple myeloma (MM). Reverse TSMR analysis revealed no association between genetically predicted B-cell malignancies and β2M. In FinnGen, β2M was found to be associated with an increased risk of DLBCL (OR: 2.098; 95% CI: 1.358-3.242; P = 8.28 × 10 -4 ; FDR = 4.14 × 10 -3 ), HL (OR: 1.581; 95% CI: 1.167-2.142; P = 3.13 × 10 -3 ; FDR = 5.22 × 10 -3 ), and FL (OR: 2.113; 95% CI: 1.292-3.455; P = 2.90 × 10 -3 ; FDR = 5.22 × 10 -3 ). However, no association was found with CLL or MM. Reverse TSMR analysis indicated that genetically predicted DLBCL, FL, and MM may perturb β2M levels. Pathway enrichment analysis suggested that the innate immune system represents a convergent biological process underlying β2M, DLBCL, and HL., Conclusions: Our findings suggested that elevated levels of β2M were associated with an increased risk of DLBCL and HL, which is potentially linked to dysfunction of the innate immune system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Wu, Zhang and Wang.)

Objective: To perform testing for cytokines involved in dermal inflammatory reactions and to document and compare the effects of an oleander extract (OE), oleandrin, and oclacitinib on biomarkers relevant to allergic reactions. The effects of these compounds under inflamed culture conditions are of direct importance to the treatment of canine atopic dermatitis., Methods: Testing involved primary canine dermal fibroblasts and the canine DH82 macrophage cell line; both cell types are important for initiating, regulating, and resolving dermal allergic reactions via cytokine communication., Results: Under inflamed conditions, OE and oleandrin downregulated key cytokines secreted by canine dermal fibroblasts and the DH82 macrophage cell line; all of which are treatment targets in dermatitis. In the DH82 macrophage cultures, the most noteworthy reductions involved IL-6, IL-12/IL-23p40, interferon-γ, tumor necrosis factor-α, VEGF, and nerve growth factor-β. Oclacitinib triggered reductions of some cytokines involved in allergic reactions, including TGF-β1, IL-12/IL-23p40, and tumor necrosis factor-α; however, these reductions were less robust than the reductions triggered by OE and oleandrin and accompanied by increases in other cytokines involved in dermal inflammation, including IL-6, interferon-γ, and nerve growth factor-β. In cultures of primary dermal fibroblasts, OE and oleandrin reduced the levels of IL-8 and monocyte chemoattractant protein-1, whereas oclacitinib had little or no effect., Conclusions: Oleander extract and oleandrin directly modulate immune responses under inflamed conditions. Moreover, OE and oleandrin appear to provide a more beneficial overall cytokine regulation than oclacitinib under inflamed culture conditions., Clinical Relevance: These results suggest that OE and oleandrin are efficacious agents to treat canine atopic dermatitis. Future studies should evaluate the efficacy of these compounds in dogs affected by atopic dermatitis.

Cholesteatoma is a potential end-stage outcome of chronic ear infections that can result in the destruction of temporal bone structures with potential resultant hearing loss, vertigo, and intracranial infectious complications. There is currently no treatment apart from surgery for this condition, and despite years of study, the histopathogenesis of this disease remains poorly understood. This review is intended to summarize our accumulated knowledge of the mechanisms of cholesteatoma development and the underlying molecular biology. Attention will be directed particularly to recent developments, covering many potential pharmacologic targets that could be used to treat this disease in the future., Competing Interests: Disclosure The authors have no conflicts of interest to report., (Published by Elsevier Inc.)

High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer., Competing Interests: DECLARATION OF INTERESTS PKS is a co-founder and member of the BOD of Glencoe Software and member of the SAB for RareCyte, NanoString, and Montai Health; he holds equity in Glencoe and RareCyte. PKS is a consultant for Merck. RD is a member of the SAB for Repare Therapeutics and is a consultant for Light Horse Therapeutics and Abbvie. The other authors declare no outside interests.

Antimicrobial peptides (AMPs) are important players of the innate immune system with a major role in the defense against invading pathogens. AMPs belonging to the family of saposin-like proteins (SAPLIPs) include the porcine NK-lysin and the human granulysin. In the zebrafish Danio rerio, transcript analyses of NK-lysin encoding genes have been reported, but biochemical characterizations at the protein level are missing so far. Here, we present the recombinant expression, purification, and characterization of one of these homologs, namely of NK-lysin A (DaNKlA). To remove the affinity tag from DaNKlA, we made use of a self-splicing intein. Recombinant DaNKlA depolarized liposomes over a broad pH range and showed a preference for negatively charged lipids. DaNKlA inhibited the growth of and killed different Gram-positive and Gram-negative bacteria, including the fish pathogenic bacterium Vibrio anguillarum, by membrane permeabilization but displayed substantially lower activity against yeast cells. Structural modelling and bioinformatic comparison of DaNKlA with characterized SAPLIPs suggest membrane destabilization accompanied by strong electrostatic interactions as the mode of action., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Surojit Karmakar, Pradipta Pal, Girdhari Lal National Centre for Cell Science (NCCS), Pune, MH, 411007, IndiaCorrespondence: Girdhari LalNational Centre for Cell Science (NCCS), NCCS Complex, Ganeshkhind, Pune, MH, 411007, IndiaTel +91-20-2570-8292Fax +91-20-2568-2259Email glal@nccs.res.inAbstract: Natural killer (NK) cells are the most potent arm of the innate immune system and play an important role in immunity, alloimmunity, autoimmunity, and cancer. NK cells recognize “altered-self” cells due to oncogenic transformation or stress due to viral infection and target to kill them. The effector functions of NK cells depend on the interaction of the activating and inhibitory receptors on their surface with their cognate ligand expressed on the target cells. These activating and inhibitory receptors interact with major histocompatibility complex I (MHC I) expressed on the target cells and make decisions to mount an immune response. NK cell immune response includes cytolytic activity and secretion of cytokines to help with the ongoing immune response. The advancement of our knowledge on the expression of inhibitory and activating molecules led us to exploit these molecules in the treatment of cancer. This review discusses the importance of activating and inhibitory receptors on NK cells and their clinical importance in cancer immunotherapy.Keywords: natural killer cells, innate immune system, oncogenic transformation, cancer, activating and inhibitory receptors

Abstract Microglia are integral mediators of innate immunity within the mammalian central nervous system. Typical microglial responses are transient, intending to restore homeostasis by orchestrating the removal of pathogens and debris and the regeneration of damaged neurons. However, prolonged and persistent microglial activation can drive chronic neuroinflammation and is associated with neurodegenerative disease. Recent evidence has revealed that abnormalities in microglial signaling pathways involving phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) may contribute to altered microglial activity and exacerbated neuroimmune responses. In this scoping review, the known and suspected roles of PI3K-AKT signaling in microglia, both during health and pathological states, will be examined, and the key microglial receptors that induce PI3K-AKT signaling in microglia will be described. Since aberrant signaling is correlated with neurodegenerative disease onset, the relationship between maladapted PI3K-AKT signaling and the development of neurodegenerative disease will also be explored. Finally, studies in which microglial PI3K-AKT signaling has been modulated will be highlighted, as this may prove to be a promising therapeutic approach for the future treatment of a range of neuroinflammatory conditions.

Nanotechnology in immunology is a prospectively developing area in fundamental and practical medicine. Cucurbiturils are macrocyclic cavitands with a definite amount of glycoluril fragments (n) that determine the size of the cavity of these compounds. Nowadays, there are six synthesized homologues: 5, 6, 7, 8, 10 and 14. They differ from each other in the portal size and the size of the cavities. They are characterized by special physicochemical and biological properties, such as biocompatibility, stability, high ability to encapsulate chemical compounds. It is known that cucurbiturils encapsulate molecules by forming guest-host complexes, which allow the substance to be released from the complex and increase the solubility of the compounds. These advantages allow using cucurbiturils as drug delivery systems. Immunomodulatory activity of cucurbiturils depends on its specific nanoscale characteristics: functional groups, shape, size, surface, solubility in various media. Each nanoparticle depending on these properties has different effects on cells. The effects of cucurbiturils can be different even for one subpopulation of cells, depending on the homologue or dosage. The interaction of innate immune cells with cucurbiturils are not yet sufficiently characterized.The aim of this study was to assess the effects of cucurbit[n]urils (n = 6, n = 7, n = 8) on innate immune cells – monocytes, NK-cells, NKT-cells.The immunological recearch included the isolation of peripheral blood mononuclear cells from healthy donors (n = 8) on the density gradient of ficoll-urografin and flow cytometry with the determination of the amount of immunocompetent cells according to the classic markers of differentiation of these cells – CD3- CD16+CD56+ for NK-cells, CD3+CD16+CD56+ for NKT-cells and CD3- CD14+ for monocytes. Monocyte activation was determined by the expression of surface HLA-DR.The cells were cultured for 72 hours with the addition of cucurbiturils CB[6], CB[7] at concentrations of 0.1 mM, 0.3 mM, 0.5 mM and CB[8] at concentration of 0.01 mM, due to its poor solubility.There were a significant decrease in the quantity of NK-cells (p < 0.01 for the test concentrations of CB[7]), an increase in the quantity of NKT-cells (p < 0.04 and p < 0.02 respectively for the concentrations of CB[6] and CB[7]). There was a tendency to increase the expression of HLA-DR on monocytes (p = 0.06 for CB[6]).Considering a variative effects of cucurbiturils, in the future it is possible to consider a possibility of using cucurbiturils as an immunomodulators, antitumor agents, in autoimmune diseases.

The freshwater snail Biomphalaria glabrata is an intermediate host of Schistosoma mansoni, the agent of human intestinal schistosomiasis. However, much is to be discovered about its innate immune system that appears as a complex black box, in which the immune cells (called hemocytes) play a major role in both cellular and humoral response towards pathogens. Until now, hemocyte classification has been based exclusively on cell morphology and ultrastructural description and depending on the authors considered from 2 to 5 hemocyte populations have been described. In this study, we proposed to evaluate the hemocyte heterogeneity at the transcriptomic level. To accomplish this objective, we used single cell RNA sequencing (scRNAseq) technology coupled to a droplet-based system to separate hemocytes and analyze their transcriptome at a unique cell level in naive Biomphalaria glabrata snails. We were able to demonstrate the presence of 7 hemocyte transcriptomic populations defined by the expression of specific marker genes. As a result, scRNAseq approach showed a high heterogeneity within hemocytes, but provides a detailed description of the different hemocyte transcriptomic populations in B. glabrata supported by distinct cellular functions and lineage trajectory. As a main result, scRNAseq revealed the 3 main population as a super-group of hemocyte diversity but, on the contrary, a great hemocytes plasticity with a probable capacity of hemocytes to engage to different activation pathways. This work opens a new field of research to understand the role of hemocytes particularly in response to pathogens, and towards S. mansoni parasites.

The innate immune system is the first line of defense against pathogens such as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The type I-interferon (IFN) response activation during the initial steps of infection is essential to prevent viral replication and tissue damage. SARS-CoV and SARS-CoV-2 can inhibit this activation, and individuals with a dysregulated IFN-I response are more likely to develop severe disease. Several mutations in different variants of SARS-CoV-2 have shown the potential to interfere with the immune system. Here, we evaluated the buffy coat transcriptome of individuals infected with Gamma or Delta variants of SARS-CoV-2. The Delta transcriptome presents more genes enriched in the innate immune response and Gamma in the adaptive immune response. Interactome and enriched promoter analysis showed that Delta could activate the INF-I response more effectively than Gamma. Two mutations in the N protein and one in the nsp6 protein found exclusively in Gamma have already been described as inhibitors of the interferon response pathway. This indicates that the Gamma variant evolved to evade the IFN-I response. Accordingly, in this work, we showed one of the mechanisms that variants of SARS-CoV-2 can use to avoid or interfere with the host Immune system.

The primary role of microglia is to maintain homeostasis by effectively responding to various disturbances. Activation of transcriptional programs determines the microglia’s response to external stimuli. In this study, we stimulated murine neonatal microglial cells with benzoyl ATP (bzATP) and lipopolysaccharide (LPS), and monitored their ability to release pro-inflammatory cytokines. When cells are exposed to bzATP, a purinergic receptor agonist, a short-lived wave of transcriptional changes, occurs. However, only combining bzATP and LPS led to a sustainable and robust response. The transcriptional profile is dominated by induced cytokines (e.g., IL-1α and IL-1β), chemokines, and their membrane receptors. Several abundant long noncoding RNAs (lncRNAs) are induced by bzATP/LPS, including Ptgs2os2, Bc1, and Morrbid, that function in inflammation and cytokine production. Analyzing the observed changes through TNF (Tumor necrosis factor) and NF-κB (nuclear factor kappa light chain enhancer of activated B cells) pathways confirmed that neonatal glial cells exhibit a distinctive expression program in which inflammatory-related genes are upregulated by orders of magnitude. The observed capacity of the microglial culture to activate a robust inflammatory response is useful for studying neurons under stress, brain injury, and aging. We propose the use of a primary neonatal microglia culture as a responsive in vitro model for testing drugs that may interact with inflammatory signaling and the lncRNA regulatory network.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

Zirconia restorations are becoming increasingly common. However, zirconia reduces the polymerization of dual-cured resin cement owing to light attenuation, resulting in residual resin monomers. This study investigated the effects of dual-cured resin cement, with incomplete polymerization owing to attenuated light through zirconia, on the inflammatory response in vitro. The dual-cured resin cement (SA Luting Multi, Kuraray) was light-irradiated through zirconia with three thickness diameters (1.0, 1.5, and 2.0 mm). The light transmittance and the degree of conversion (DC) of the resin cement significantly decreased with increasing zirconia thickness. The dual-cured resin cement in 1.5 mm and 2.0 mm zirconia and no-irradiation groups showed significantly higher amounts of hydroxyethylmethacrylate and triethyleneglycol dimethacrylate elution and upregulated gene expression of proinflammatory cytokines IL-1β and IL-6 from human gingival fibroblasts (hGFs) and TNFα from human monocytic cells, compared with that of the 0 mm group. Dual-cured resin cement with lower DC enhanced intracellular reactive oxygen species (ROS) levels and activated mitogen-activated protein (MAP) kinases in hGFs and monocytic cells. This study suggests that dual-cured resin cement with incomplete polymerization induces inflammatory responses in hGFs and monocytic cells by intracellular ROS generation and MAP kinase activation.

Background: For over a century, scientists have studied host-pathogen interactions between the crayfish plague disease agent Aphanomyces astaci and freshwater crayfish. It has been hypothesised that North American crayfish hosts are disease-resistant due to the long-lasting coevolution with the pathogen. Similarly, the increasing number of latent infections reported in the historically sensitive European crayfish hosts seems to indicate that similar coevolutionary processes are occurring between European crayfish and A. astaci. Our current understanding of these host-pathogen interactions is largely focused on the innate immunity processes in the crayfish haemolymph and cuticle, but the molecular basis of the observed disease-resistance and susceptibility remain unclear. To understand how coevolution is shaping the host's molecular response to the pathogen, susceptible native European noble crayfish and invasive disease-resistant marbled crayfish were challenged with two A. astaci strains of different origin: a haplogroup A strain (introduced to Europe at least 50 years ago, low virulence) and a haplogroup B strain (signal crayfish in lake Tahoe, USA, high virulence). Here, we compare the gene expression profiles of the hepatopancreas, an integrated organ of crayfish immunity and metabolism. Results: We characterised several novel innate immune-related gene groups in both crayfish species. Across all challenge groups, we detected 412 differentially expressed genes (DEGs) in the noble crayfish, and 257 DEGs in the marbled crayfish. In the noble crayfish, a clear immune response was detected to the haplogroup B strain, but not to the haplogroup A strain. In contrast, in the marbled crayfish we detected an immune response to the haplogroup A strain, but not to the haplogroup B strain. Conclusions: We highlight the hepatopancreas as an important hub for the synthesis of immune molecules in the response to A. astaci. A clear distinction between the innate immune response in the marbled crayfish and the noble crayfish is the capability of the marbled crayfish to mobilise a higher variety of innate immune response effectors. With this study we outline that the type and strength of the host immune response to the pathogen is strongly influenced by the coevolutionary history of the crayfish with specific A. astaci strains. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a widespread disease associated with high rates of disability and mortality. COPD is characterized by chronic inflammation in the bronchi as well as systemic inflammation, which contributes significantly to the clinically heterogeneous course of the disease. Lipid metabolism disorders are common in COPD, being a part of its pathogenesis. High-density lipoproteins (HDLs) are not only involved in lipid metabolism, but are also part of the organism's immune and antioxidant defense. In addition, HDL is a versatile transport system for endogenous regulatory agents and is also involved in the removal of exogenous substances such as lipopolysaccharide. These functions, as well as information about lipoprotein metabolism disorders in COPD, allow a broader assessment of their role in the pathogenesis of heterogeneous and comorbid course of the disease. [ABSTRACT FROM AUTHOR]

The innate immune system is the host's first line of defense against pathogens. Toll-like receptors (TLRs) are pattern recognition receptors that mediate recognition of pathogen-associated molecular patterns. TLRs also activate signaling transduction pathways involved in host defense, inflammation, development, and the production of inflammatory cytokines. Innate immunodeficiencies associated with defective TLR signaling include mutations in NEMO, IKBA, MyD88, and IRAK4. Other innate immune defects have been associated with susceptibility to herpes simplex encephalitis, viral infections, and mycobacterial disease, as well as chronic mucocutaneous candidiasis and epidermodysplasia verruciformis. Phagocytes and natural killer cells are essential members of the innate immune system and defects in number and/or function of these cells can lead to recurrent infections. Complement is another important part of the innate immune system. Complement deficiencies can lead to increased susceptibility to infections, autoimmunity, or impaired immune complex clearance. The innate immune system must work to quickly recognize and eliminate pathogens as well as coordinate an immune response and engage the adaptive immune system. Defects of the innate immune system can lead to failure to quickly identify pathogens and activate the immune response, resulting in susceptibility to severe or recurrent infections. [ABSTRACT FROM AUTHOR]

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 a-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: DCSIGN 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 SARSCoV-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 proinflammatory cytokines and chemokines such as TNF-a, IFN-a, IL-1b, IL-6, IL-8, and RANTES (as well as NF-kB) 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. [ABSTRACT FROM AUTHOR]

Within the cytoplasm of mammalian cells is a protein called cyclic GMP‐AMP synthase (cGAS), which acts to defend against infection and other threats to the host. cGAS operates in this manner through its ability to detect a molecular occurrence that should not exist in healthy cells – the existence of DNA in the cytosol. Upon DNA binding, cGAS synthesizes cyclic GMP‐AMP (cGAMP), a cyclic dinucleotide that activates the endoplasmic reticulum‐localized protein stimulator of interferon genes (STING). STING‐mediated signaling culminates in host defensive responses typified by inflammatory cytokine and interferon expression, and the induction of autophagy. Studies over the past several years have established a consensus in the field of the enzymatic activities of cGAS in vitro, as it relates to DNA‐induced production of cGAMP. However, much additional work is needed to understand the regulation of cGAS functions within cells, where multiple sources of DNA can create a problem of self and non‐self discrimination. In this review, we provide an overview of how the cGAS‐STING pathway mediates innate immune responses during infection and other cellular stresses. We then highlight recent progress in the understanding of the increasingly diverse ways in which this DNA‐sensing machinery is regulated inside cells, including how cGAS remains inactive to host‐derived DNA under conditions of homeostasis. [ABSTRACT FROM AUTHOR]