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Results for “Immunology”

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bioRxiv2018

Osmolality controls the expression of cathelicidin antimicrobial peptide in human macrophages

An imbalance between extracellular and intracellular fluid osmolality causes osmotic stress and affects cellular homeostasis. Recent research suggests that osmotic stress is also associated with various innate and adaptive immune responses. Here we present the surprising finding that osmolality tightly controls the expression of cathelicidin antimicrobial peptide (CAMP) in human macrophages. CAMP expression is strongly upregulated under hyperosmotic conditions and downregulated under hypoosmotic conditions. We also provide evidence that this osmolality-mediated antimicrobial response is dependent on nuclear factor of activated T-cells 5 (NFAT5) and mitogen-activated protein kinase (MAPK) p38. Finally, Toll-like receptor (TLR) activation inhibits osmolality-mediated expression of CAMP in human macrophages, suggesting that this osmolality-dependent regulation of CAMP is more relevant under homeostatic conditions, rather than during acute infections. This study expands our knowledge of the regulation of human antimicrobial peptides and highlights osmolality as an important and independent factor shaping host innate immune homeostasis.

immunology↗

bioRxiv2018

Hepatitis B Virus Inhibits Neutrophil Extracellular Traps Release by Modulating Reactive Oxygen Species Production and Autophagy

Neutrophils, an important component of the innate immune system, release extracellular traps (NETs) to eliminate invaded pathogens by trapping and killing microbes. A dysfunctional innate immune response is a major cause of persistent hepatitis B virus (HBV) infection. HBV has been shown to reduce neutrophil responses. The objectives of the present study were to determine whether HBV influenced NETs release and to identify the underlying mechanisms. Primary neutrophils and circulating blood samples were collected from 40 patients with a chronic hepatitis B infection (CHB) and 40 healthy controls to detect NETs release using a Quant-iT Pico Green dsDNA assay and to determine the levels of HBV-DNA and HBV markers. NETs release was decreased in patients with a CHB infection, and hepatitis B surface antigen, hepatitis B e antigen and hepatitis B core antibody levels negatively correlated with NETs release. The Quant-iT Pico Green dsDNA assay and western blotting were used to examine the effect of HBV proteins (HBV X protein, HBV C protein, HBV E protein and HBV S protein) on NETs release in vitro. Based on the flow cytometry and western blot data, HBV C protein and HBV E protein inhibited NETs release by decreasing reactive oxygen species (ROS) production and autophagy. Overall, HBV may inhibit NETs release by modulating ROS production and autophagy to escape the immune system and promote the establishment of a chronic infection.

immunology↗

bioRxiv2018

Loss of the Wnt/β-catenin pathway in microglia of the developing brain drives pro-inflammatory activation leading to white matter injury

Microglia of the developing brain have unique functional properties but how their activation states is regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain with multiple models of neuroinflammation-mediated injury and primary human microglia we found that a reduction in Wnt/{beta}-catenin signalling is necessary and sufficient to drive an oligodendrocyte-injurious microglial phenotype. We validated in a cohort of preterm born infants that genomic variation in the WNT pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a BBB penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.

immunology↗

bioRxiv2018

Pellino 1 Communicates Intercellular Signaling in Chronic Skin Inflammatory Microenvironment

Chronic skin inflammation including psoriasis is a multisystem disease, affecting more than 5% of the general population. Here we show that Pellino 1 (Peli1), a signal-responsive ubiquitin E3 ligase, is highly up-regulated in human psoriatic skin lesions and that increased Peli1 expression correlates with the immunopathogenesis of psoriasis-like chronic skin inflammatory disease. Interestingly, Peli1 directly interacts with interferon regulatory factor 4 (IRF4, a transcription factor that plays pivotal roles in proliferation and cytokine production) and induces lysine 63-mediated ubiquitination. Peli1-mediated IRF4 ubiquitination appears to be a common systemic signaling mechanism shared by lesional keratinocytes, dendritic cells, macrophages, and T cells, generating a feedback relationship between keratinocyte and Th17 cell responses. Conversely, inhibition of Peli1 interferes with IRF4 induction and attenuates immunopathogenic signaling in the psoriasis. In summary, Peli1-mediated ubiquitination is a common immunopathogenic intercellular signaling in psoriasis-like chronic skin inflammatory microenvironment. Thus, targeting Peli1 could be used as a potential strategy for psoriasis treatment.

immunology↗

bioRxiv2018

TGFβ stimulates fibroblast-like synovial cells to produce ED-A fibronectin in osteoarthritis

IntroductionThe pathophysiology of osteoarthritis (OA) involves wear and tear, and a state of low-grade inflammation. Wear and tear leads to tissue degradation and tissue repair responses, including tissue growth factor beta (TGF{beta})-induced myofibroblast production of extracellular matrix (ECM). Fibronectins are an essential part of the ECM, and injection of fibronectin fragments into rabbit joints is a previously established animal model of OA. Alternatively-spliced fibronectin contains the ED-A domain (ED-A FN) and has been shown to activate Toll-like receptor 4. In this study, we tested the hypothesis that FN fragments containing the ED-A domain could be one mechanism transducing mechanical events into inflammatory signals in OA.\n\nMethodsSamples of synovial membrane and cartilage were obtained from patients with knee OA undergoing joint replacement surgery. Immunostaining for ED-A FN and the myofibroblast marker alpha smooth muscle actin (SMA) was performed on synovial membranes and fibroblast-like synovial cells (FLS). FLS were stimulated with TGF{beta}, TNF, lipopolysaccharide, IL-6, OA synovial fluid, or chondrocyte lysate, and analyzed for ED-A FN. Synovial cells isolated by enzymatic digestion and human monocyte-derived macrophages (MDM) were incubated with recombinant ED-A FN, plasmin, cellular FN, or cellular FN digested with plasmin; and culture supernatants were analyzed for MCP-1 and TNF.\n\nResultsWe hypothesized that ED-A FN is produced by OA FLS in response to factors found in the OA synovial joint. Indeed, the production of ED-A FN by OA FLS was increased by TGF{beta}, OA synovial fluid, and lysed chondrocytes in all experiments (n=3). ED-A FN co- localized with the myofibroblast marker SMA in both the OA FLS (n=3) and in the OA synovial membranes (n=8). We further hypothesized that ED-A FN expression is associated with cellular density and expression of inflammatory molecules in OA. ED-A FN staining was associated with both number of lining layer cells (rho=0.85 and p=0.011) and sublining cells (rho=0.88 and p=0.007) in the OA synovium (n=8), and co-localized with both MCP-1 and TNF (n=5). Recombinant ED-A FN increased the production of both MCP-1 and TNF by MDM (n=3) and OA FLS (n=3). Finally, we demonstrated that the FN fragments containing the ED-A domain generated the same production of both MCP-1 and TNF as recombinant ED-A FN.\n\nConclusionThe disease process in OA shares features with the chronic wound healing response including myofibroblast differentiation and production of mediators that promote myofibroblast production of ED-A FN. We show that recombinant and plasmin-derived ED-A fragments stimulate FLS and MDM to produce pro-inflammatory mediators. Our findings support utilizing ED-A FN for drug delivery or therapeutic targeting of the formation of ED- A FN or the enzymatic fragmentation of FN to reduce pro-inflammatory responses in OA.

immunology↗

bioRxiv2018

Peptide length distribution and multiple specificity in naturally presented HLA-I ligands

HLA-I molecules bind short peptides and present them for recognition by CD8+ T cells. The length of HLA-I ligands typically ranges from 8 to 12 amino acids, but variability is observed across different HLA-I alleles. Here we collected recent in-depth HLA peptidomics data, including 12 newly generated HLA peptidomes (31,896 unique peptides) from human meningioma samples, to analyze the peptide length distribution and multiple specificity across 84 different HLA-I alleles. We observed a clear clustering of HLA-I alleles with distinct peptide length distributions, which enabled us to study the structural basis of peptide length distributions and predict peptide length distributions from HLA-I sequences. We further identified multiple specificity in several HLA-I molecules and validated these observations with binding assays. Explicitly modeling peptide length distribution and multiple specificity improved predictions of naturally presented HLA-I ligands, as demonstrated in an independent benchmarking based on the new human meningioma samples.

immunology↗

bioRxiv2018

Vasculature-associated adipose tissue macrophages dynamically adapt to inflammatory and metabolic challenges

Tissue-resident macrophages comprise the most abundant immune cell population in healthy adipose tissue. Adipose tissue macrophage populations change during metabolic stress and ageing, and are thought to contribute to the pathogenesis of obesity. Here, we studied adipose tissue macrophage subpopulations in the steady state, and in response to nutritional and infectious challenges.\n\nUsing comprehensive cell-surface-based and gene expression analyses, we found that tissue-resident macrophages from healthy epididymal white adipose tissue (eWAT) tightly associate with blood vessels, displaying a very high endocytic capacity. We refer to these cells as Vasculature-associated Adipose tissue Macrophages (VAMs). Chronic high fat diet (HFD) feeding results in the accumulation of a monocyte-derived CD11c+CD64+ double positive (DP) macrophage eWAT population with a predominant anti-inflammatory gene profile, but reduced endocytic function. In contrast, fasting rapidly and reversibly leads to VAM depletion, while acute inflammatory stress induced by pathogens transiently depletes VAMs and simultaneously boosts DP macrophage accumulation. Our results indicate that adipose tissue macrophage populations adapt to metabolic stress and inflammation, suggesting an important role for these cells in restoring homeostasis.

immunology↗

bioRxiv2018

Anti-V2 Antibody Deficiency in Individuals Infected With HIV-1

The positive correlation of high levels of plasma anti-V2 antibodies (Abs) with protective immunity in the Phase III anti-HIV RV144 vaccine trial generated interest in the induction of these Abs for HIV vaccine development. We analyzed plasma samples from 79 chronically infected Cameroonian individuals for Ab reactivity against three V1V2 fusion proteins and five cyclic V2 peptides and found that HIV-1 infection induces different levels of anti-V2 Abs. While the majority of plasma samples reacted strongly with one or more V2 antigens, 10% (8) of the samples were nonreactive. Deficiency of anti-V2 Abs was consistently found in longitudinal plasma samples tested over 8 to 54 months of HIV infection. There was a strong correlation between binding activities of plasma anti-V2 Abs and anti-gp120 and anti-gp41 Abs, suggesting that deficiency of V2 Abs could be related, in part, to a limited ability to elicit strong Ab responses. Analysis of gp120 sequences revealed that the V2 region of viruses from donors with V2-deficient versus V2-reactive Abs displayed a tendency toward longer length, more glycans, and lower isoelectric point and charge. No differences between these two patient groups were noted in the same parameters measured in the V1 region. These data suggest that immunogens containing a shorter V2 region with fewer glycosylation sites and higher electrostatic charges would be beneficial for induction of anti-V2 Abs, but the ability to mount a strong general Ab response to HIV-1 appears to be a dominant factor.\n\nIMPORTANCEThe results of the RV144 vaccine clinical trial showed a correlation between plasma Abs against a V1V2 fusion protein and a decreased risk of acquiring HIV-1 infection. This turned the focus of some HIV vaccine design to the induction of elevated levels of anti-V2 Abs to increase vaccine efficacy. In plasma samples from Cameroonian individuals infected with HIV-1, we observed broad variations in levels of anti-V2 Abs, and 8 of the 79 plasma samples tested displayed substantial deficiency of V2 Abs. Sequence analysis of the V2 region from plasma viruses and multivariate analyses of V2 characteristics showed a significant difference in several features between V2-deficient and V2-reactive plasma Abs. These results suggest that HIV vaccine immunogens containing a V2 region with shorter length, fewer glycosylation sites, and higher electrostatic charges may be beneficial for induction of a higher level of anti-V2 Abs and thus contribute to HIV vaccine efficacy.

immunology↗

bioRxiv2018

Single haplotype admixture models using large scale HLA genotype frequencies to reproduce human admixture

The Human Leukocyte Antigen (HLA) is the most polymorphic region in humans. Anthropologists use HLA to trace populations migration and evolution. However, recent admixture between populations masks the ancestral haplotype frequency distribution.\n\nWe present an HLA-based method based on high-resolution HLA haplotype frequencies to resolve population admixture using a non-negative matrix factorization formalism and validated using haplotype frequencies from 56 populations. The result is a minimal set of original populations decoding roughly 90% of the total variance in the studied admixtures. These original populations agree with the geographical distribution, phylogenies and recent admixture events of the studied groups.\n\nWith the growing population of multi-ethnic individuals, the matching process for stem-cell and solid organ transplants is becoming more challenging. The presented algorithm provides a framework that facilitates the breakdown of highly admixed populations into original groups, which can be used to better match the rapidly growing population of multi-ethnic individuals worldwide.\n\nAuthor SummaryHuman Leukocyte Antigen (HLA) is known to be the most polymorphic region in the human genome. Anthropologists frequently use HLA to trace migration and evolution of different populations. This is due to the high linkage among HLA genes leading to the transmission of intact haplotypes from parents to offspring, hence preserving key population ancestral features.\n\nWe developed a new HLA-based method to identify admixture models in mixed populations using high-resolution HLA haplotype frequencies. Our results highlight that a single highly polymorphic locus can contain enough information to map clearly human admixture and the population genetics of the different human populations, and reproduces results based on SNP arrays.\n\nThe presented algorithm is validated using haplotype frequencies sampled from 56 worldwide populations. Under such factorization we demonstrate that 90% of the variance in these populations can be explained using a much-reduced set of 8 ethnic groups. We demonstrate that the estimated ethnic groups and admixture models agree with the geographical distribution, population phylogenies and recent historic admixture events of the studied populations.

immunology↗

bioRxiv2018

Identification and Characterisation of the CD40-Ligand of Sigmodon hispidus

Cotton rats are an important animal model to study infectious diseases. They have demonstrated higher susceptibility to a wider variety of human pathogens than other rodents and are also the animal model of choice for pre-clinical evaluations of some vaccine candidates. However, the genome of cotton rats remains to be fully sequenced, with much fewer genes cloned and characterised compared to other rodent species. Here we report the cloning and characterization of CD40 ligand, whose human and murine counterparts are known to be expressed on a range of cell types including activated T cells and B cells, dendritic cells, granulocytes, macrophages and platelets and exerts a broad array of immune responses. The cDNA for cotton rat CD40L we isolated is comprised of 1104 nucleotides with an open reading frame (ORF) of 783bp coding for a 260 amino acid protein. The recombinant cotton rat CD40L protein was recognized by an antibody against mouse CD40L. Moreover, it demonstrated functional activities on immature bone marrow dendritic cells by upregulating surface maturation markers (CD40, CD54, CD80, and CD86), and increasing IL-6 gene and protein expression. The availability of CD40L gene identity could greatly facilitate mechanistic research on pathogen-induced-immunopathogenesis and vaccine-elicited immune responses.

immunology↗

bioRxiv2018

Inhibition of thrombocyte activation restores protective immunity to mycobacterial infection

Infection-induced thrombocytosis is a clinically important complication of tuberculosis (TB). Recent studies have separately highlighted a correlation of platelet activation with TB severity and utility of aspirin as a host-directed therapy for TB that modulates the inflammatory response. Here we investigate the possibility that the beneficial effects of aspirin are related to an anti-platelet mode of action. We utilize the zebrafish-Mycobacterium marinum model to show mycobacteria drive host hemostasis through the formation of granulomas. Treatment of infected zebrafish with aspirin or platelet-specific glycoprotein IIb/IIIa inhibitors reduced mycobacterial burden demonstrating a detrimental role for infection-induced thrombocyte activation. We found platelet inhibition reduced thrombocyte-macrophage interactions and restored indices of macrophage-mediated immunity to mycobacterial infection. Pathological thrombocyte activation and granuloma formation were found to be intrinsically linked illustrating a bidirectional relationship between host hemostasis and TB pathogenesis. Our study illuminates platelet activation as an efficacious target of anti-platelets drugs including aspirin, a widely available and affordable host-directed therapy candidate for tuberculosis.\n\nKey PointsO_LIInhibition of thrombocyte activation improves control of mycobacterial infection.\nC_LIO_LIInhibition of thrombocyte activation reduces thrombocyte-macrophage interactions and improves indices of macrophage immune function against mycobacterial infection.\nC_LI

immunology↗

bioRxiv2018

Application of fuzzy inference systems to parameter optimization of a biochemical rule-based model

Our main contribution is an efficient machine learning approach to fitting parameters of a biological model. We study the binding of the shrimp protein Pen a 1 with antibody-receptor complexes because this process is important in understanding the allergic response. Previously, we developed a BioNetGen model that simulates this process. We previously developed a method for encoding steric effects via the optimization of two parameters: the cutoff distance and the rule rate. We optimized these two parameters by fitting the output to that generated by a 3D robotics-inspired Monte Carlo simulation that explicitly represents molecular geometry.\n\nIn this work, we aim to optimize the parameters for our BioNetGen model using an efficient method: an adaptive-network-based fuzzy inference system implemented in MAT-LAB. We want to develop fuzzy systems that can accurately predict the rule binding rate and cutoff distance given a residual-sum-of-squares value or a probability distribution. We construct the fuzzy systems using fuzzy c-means clustering with existing data from BioNetGen model parameter scans as the training data. We create and test fuzzy systems with various input data and number of clusters, and analyze their performance with regard to the effective optimization of our rule-based model. We find that the fuzzy system that uses a residual-sum-of-squares value as the input value performs acceptably well. However, the performance of the fuzzy systems that use probabilities as their input values perform inconsistently in our tests.\n\nThe results of this study suggest that the system that uses a residual-sum-of-squares value as the input value could potentially be used to find an adequate fit for our biochemical model. However, the systems that use probabilities as their input values need further development to improve the consistency and reliability of their output. Testing more values for other clustering parameters other than the number of clusters may accomplish this. Further research could also include similar studies using other training or clustering algorithms. This methodology could be modified for use with fitting other biological models.

immunology↗

bioRxiv2018

The damage signal IL-33 promotes a focal protective myeloid cell response to Toxoplasma gondii in the brain

Understanding how invading pathogens are sensed within the brain is necessary to uncover how effective immune response are mounted in immunoprivileged sites. The eukaryotic parasite Toxoplasma gondii colonizes the brain of its hosts and initiates robust immune cell recruitment, but little is known about innate recognition of T. gondii within brain tissue. The host damage signal IL-33 is one protein that has been implicated in control of chronic T. gondii infection, but the specific impact of IL-33 signaling within the brain is unclear. Here, we show that IL-33 is expressed by oligodendrocytes and astrocytes during T. gondii infection, is released into the cerebrospinal fluid of T. gondii-infected animals, and is required for control of infection. IL-33 signaling promotes chemokine expression within brain tissue and is required for the recruitment of peripheral anti-parasitic immune cells, including IFN-{gamma}-expressing T cells and iNOS-expressing monocytes. Importantly, we find that the beneficial effects of IL-33 during chronic infection are not a result of signaling on infiltrating immune cells, but rather on radio-resistant responders, and specifically, astrocytes. Mice with IL-33R-deficient astrocytes fail to promote an adaptive immune response in the CNS and control parasite burden, demonstrating that astrocytes can directly respond to IL-33 in vivo. Together, these results indicate a brain-specific mechanism by which IL-33 is released and sensed locally, to engage the peripheral immune system in controlling a neurotropic pathogen.

immunology↗

bioRxiv2018

Both cell-intrinsic and environmental factors constrain speed and persistence in T cell migration

Cell migration is astoundingly diverse. Molecular signatures, cell-cell and cell-matrix interactions, and environmental structures each play their part in shaping cell motion, yielding numerous different cell morphologies and migration modes. Nevertheless, in recent years, a simple unifying law was found to describe cell migration across many different cell types and contexts: faster cells turn less frequently. Given this universal coupling between speed and persistence (UCSP), from a modelling perspective it is important to know whether computational models of cell migration capture this speed-persistence link. Here, we present an in-depth characterisation of an existing Cellular Potts Model (CPM). We first show that this model robustly reproduces the UCSP without having been designed for this task. Instead, we show that this fundamental law of migration emerges spontaneously through a crosstalk of intracellular mechanisms, cell shape, and environmental constraints, resembling the dynamic nature of cell migration in vivo. Our model also reveals how cell shape dynamics can further constrain cell motility by limiting both the speed and persistence a cell can reach, and how a rigid environment such as the skin can restrict cell motility even further. Our results further validate the CPM as a model of cell migration, and shed new light on the speed-persistence coupling that has emerged as a fundamental property of migrating cells. SIGNIFICANCEThe universal coupling between speed and persistence (UCSP) is the first general quantitative law describing motility patterns across the versatile spectrum of migrating cells. Here, we show - for the first time - that this migration law emerges spontaneously in an existing, highly popular computational model of cell migration. Studying the UCSP in entirely different model frameworks, not explicitly built with this law in mind, can help uncover how intracellular dynamics, cell shape, and environment interact to produce the diverse motility patterns observed in migrating cells.

immunology↗

bioRxiv2018

Recovered and dead outcome patients caused by influenza A (H7N9) virus infection show different pro-inflammatory cytokine dynamics during disease progress and its application in real-time prognosis

The persistent circulation of influenza A(H7N9) virus within poultry markets and human society leads to sporadic epidemics of influenza infections. Severe pneumonia and acute respiratory distress syndrome (ARDS) caused by the virus lead to high morbidity and mortality rates in patients. Hyper induction of pro-inflammatory cytokines, which is known as \"cytokine storm\", is closely related to the process of viral infection. However, systemic analyses of H7N9 induced cytokine storm and its relationship with disease progress need further illuminated. In our study we collected 75 samples from 24 clinically confirmed H7N9-infected patients at different time points after hospitalization. Those samples were divided into three groups, which were mild, severe and fatal groups, according to disease severity and final outcome. Human cytokine antibody array was performed to demonstrate the dynamic profile of 80 cytokines and chemokines. By comparison among different prognosis groups and time series, we provide a more comprehensive insight into the hypercytokinemia caused by H7N9 influenza virus infection. Different dynamic changes of cytokines/chemokines were observed in H7N9 infected patients with different severity. Further, 33 cytokines or chemokines were found to be correlated with disease development and 11 of them were identified as potential therapeutic targets. Immuno-modulate the cytokine levels of IL-8, IL-10, BLC, MIP-3a, MCP-1, HGF, OPG, OPN, ENA-78, MDC and TGF-{beta} 3 are supposed to be beneficial in curing H7N9 infected patients. Apart from the identification of 35 independent predictors for H7N9 prognosis, we further established a real-time prediction model with multi-cytokine factors for the first time based on maximal relevance minimal redundancy method, and this model was proved to be powerful in predicting whether the H7N9 infection was severe or fatal. It exhibited promising application in prognosing the outcome of a H7N9 infected patients and thus help doctors take effective treatment strategies accordingly.

immunology↗

bioRxiv2018

Critical role of post-transcriptional regulation for IFN-γ in tumor-infiltrating T cells

Protective T cell responses against tumors require the production of Interferon gamma (IFN-{gamma}). However, tumor-infiltrating T cells (TILs) gradually lose their capacity to produce IFN-{gamma} and therefore fail to clear malignant cells. Dissecting the underlying mechanisms that block cytokine production is thus key for improving T cell products. Here we show that although TILs express substantial levels of Ifng mRNA, post-transcriptional mechanisms impede the production of IFN-{gamma} protein due to loss of mRNA stability. CD28 triggering, but not PD1 blocking antibodies, effectively restores the stability of Ifng mRNA. Intriguingly, TILs devoid of AU-rich elements within the 3untranslated region maintain stabilized Ifng mRNA and produce more IFN-{gamma} protein than wild-type TILs. This sustained IFN-{gamma} production translates into effective suppression of tumor outgrowth, which is almost exclusively mediated by direct effects on the tumor cells. We therefore conclude that post-transcriptional mechanisms could be modulated to potentiate effective T cell therapies in cancer.

immunology↗

bioRxiv2018

The chemokine receptor CXCR2 contributes to murine adipocyte development

Chemokines are members of a large family of chemotactic cytokines that signal through their receptors to mediate leukocyte recruitment during inflammation and homeostasis. The chemokine receptor CXCR2 has largely been associated with neutrophil recruitment. However, there is emerging evidence of roles for chemokines and their receptors in processes other than leukocyte migration. We have previously demonstrated that CXCR2 KO mice have thinner skin compared to wild type mice. Herein we demonstrate that this is due to a thinner subcutaneous adipose layer, as a result of fewer and smaller individual adipocytes. We observe a similar phenotype in other fat depots and present data that suggests this may be due to reduced expression of adipogenesis related genes associated with adipocyte specific CXCR2 signalling. Interestingly, this phenotype is evident in female, but not male, CXCR2 KO mice. These findings expand our understanding of non-leukocyte related chemokine receptor functions and help to explain some previously observed adipose-related phenotypes in CXCR2 KO mice.

immunology↗

bioRxiv2018

Activation of RIG-I-mediated antiviral signaling triggers autophagy through the MAVS-TRAF6-Beclin-1 signaling axis

Autophagy has been implicated in innate immune responses against various intracellular pathogens. Recent studies have reported that autophagy can be triggered by pathogen recognizing sensors, including Toll-like receptors and cyclic guanosine monophosphate-adenosine monophosphate synthase, to participate in innate immunity. In the present study, we examined whether the RIG-I signaling pathway, which detects viral infections by recognizing viral RNA, triggers the autophagic process. The introduction of polyI:C into the cytoplasm, or Sendai virus infection, significantly induced autophagy in normal cells but not in RIG-I-deficient cells. PolyI:C transfection or Sendai virus infection induced autophagy in the cells lacking type-I interferon signaling. This demonstrated that the effect was not due to interferon signaling. RIG-I-mediated autophagy diminished by the deficiency of mitochondrial antiviral signaling protein (MAVS) or tumor necrosis factor receptor-associated factor (TRAF)6, showing that the RIG-I-MAVS-TRAF6 signaling axis was critical for RIG-I-mediated autophagy. We also found that Beclin-1 was translocated to the mitochondria, and it interacted with TRAF6 upon RIG-I activation. Furthermore, Beclin-1 underwent K63-polyubiquitination upon RIG-I activation, and the ubiquitination decreased in TRAF6-deficient cells. This suggests that the RIG-I-MAVS-TRAF6 axis induced K63-linked polyubiquitination of Beclin-1, which has been implicated in triggering autophagy. Collectively, the results of this study show that the recognition of viral infection by RIG-I is capable of inducing autophagy to control viral replication. As deficient autophagy increases the type-I interferon response, the induction of autophagy by the RIG-I pathway might also contribute to preventing an excessive interferon response as a negative-feedback mechanism.\n\nImportanceMammalian cells utilize various innate immune sensors to detect pathogens. Among those sensors, RIG-I recognizes viral RNA to detect intracellular viral replication. Although cells experience diverse physiological changes upon viral infection, studies to understand the role of RIG-I signaling have focused on the induction of type-I interferon. Autophagy is a process that sequesters cytosolic regions and degrades the contents to maintain cellular homeostasis. Autophagy participates in the immune system, and has been known to be triggered by some innate immune sensors, such as TLR4 and cGAS. We demonstrated that autophagy can be triggered by the activation of RIG-I. In addition, we also proved that MAVS-TRAF6 downstream signaling is crucial for the process. Beclin-1, a key molecule in autophagy, is translocated to mitochondria, where it undergoes K63-ubiquitination in a TRAF6-dependent manner upon RIG-I activation. As autophagy negatively regulates RIG-I-mediated signaling, the RIG-I-mediated activation of autophagy may function as a negative-feedback mechanism.

immunology↗