β-arrestin-2 (β-arr2) is a scaffolding protein of the arrestin family with a wide variety of cellular functions. Recent studies have demonstrated differential roles for β-arr2 in inflammation following endotoxemia and cecal ligation and puncture (CLP) models of sepsis. Because CLP-induced inflammation involves response to fecal contents and necrotic cecum in addition to microbial challenge, in this study, we examined the role of β-arr2 in an exclusively polymicrobial infection (PMI) model. In addition, we examined the role of gene dosage of β-arr2 in polymicrobial sepsis. Our studies demonstrate that β-arr2 is a negative regulator of systemic inflammation in response to polymicrobial infection and that one allele is sufficient for this process. Our results further reveal that loss of β-arr2 leads to increased neutrophil sequestration and overt inflammation specifically in the lungs following polymicrobial infection. Consistent with this, specific NF-κB and mitogen-activated protein kinase (MAPK) signaling pathways were differentially activated in the β-arr2 knockout (KO) mice lungs compared to the wild type (WT) following PMI. Associated with enhanced inflammation in the KO mice, PMI-induced mortality was also significantly higher in KO mice than in WT mice. To understand the differential role of β-arr2 in different sepsis models, we used cell culture systems to evaluate inflammatory cytokine production following endotoxin and polymicrobial stimulation. Our results demonstrate cell-type- as well as stimulus-specific roles for β-arr2 in inflammation. Taken together, our results reveal a negative regulatory role for β-arr2 in polymicrobial infection-induced inflammation and further demonstrate that one allele of β-arr2 is sufficient to mediate most of these effects.
Abstract Campylobacter jejuni is the most common bacterial cause of gastroenteritis worldwide. C. jejuni infection has also been causally linked with development of the peripheral neuropathy called Guillain Barré Syndrome (GBS). We have previously shown that C. jejuni isolates from human enteritis patients induce a Type1/17 cytokine dependent colitis response in IL-10-/- mice. In contrast, isolates from human GBS patients colonize the IL-10-/- mice without inducing colitis but instead induce autoantibody elicitation targeted against peripheral nerve antigens. We show here that the autoantibody response is dependent upon blunted Type1/17 but enhanced Type2 cytokine production by T helper cells. Autoantibody elicitation also correlated with enhanced macrophage infiltration in the sciatic nerve and its dorsal root ganglia. Autoantibodies and these histological changes were significantly decreased in mice depleted of IL-4, without leading to colitis induction. Histological damage in the sciatic nerve was associated with abnormal gait and hind limb movements in the IL-10-/- mice, consistent with this syndrome’s manifestation in humans. Furthermore, we show here that Siglec1 is a central antigen presenting cell receptor that mediates GBS but not colitogenic isolate uptake, T cell differentiation and autoantibody elicitation. Therefore, this is the first mouse model of an autoimmune disease induced directly by a bacterium and it is dependent upon Siglec1 and IL-4 axes.
Summary The interleukin ( IL )‐1 family of cytokines is currently comprised of 11 members that have pleiotropic functions in inflammation and cancer. IL ‐1α and IL ‐1β were the first members of the IL ‐1 family to be described, and both signal via the same receptor, IL ‐1R. Over the last decade, much progress has been made in our understanding of biogenesis of IL ‐1β and its functions in human diseases. Studies from our laboratory and others have highlighted the critical role of nod‐like receptors ( NLR s) and multi‐protein complexes known as inflammasomes in the regulation of IL ‐1β maturation. Recent studies have increased our appreciation of the role played by IL ‐1α in inflammatory diseases and cancer. However, the mechanisms that regulate the production of IL ‐1α and its bioavailability are relatively understudied. In this review, we summarize the distinctive roles played by IL ‐1α in inflammatory diseases and cancer. We also discuss our current knowledge about the mechanisms that control IL ‐1α biogenesis and activity, and the major unanswered questions in its biology.
The aim of this work is to estimate the electro-magnetic field at a given spatial point within the cavity as well as the spin of the electron bound to its nucleus placed within the cavity. We calculate it using the Hudson-Parthasarathy Schrödinger quantum stochastic differential equation (HPS-QSDE), Plot Noise-to-Signal ratio (NSR) for cavity field observable and spin of electron which validate the effectiveness of the Belavkin quantum filter using MATLAB.
Abstract The cross-talk between innate immune sensors and commensal microbes in the gut is crucial for maintaining intestinal barrier homeostasis. Fungi represent a major component of the resident gut flora, and fungal diversity narrows during colitis and colorectal cancer pathogenesis. Mutations in the genes that encode molecules involved in the fungal sensing pathways are associated with an increased risk of developing colitis and colorectal cancer. However, the precise roles of gut fungi and associated immune recognition cascade in colitis and colorectal tumorigenesis are not well established. We show here the role of commensal fungal sensing by CLR signaling pathway in the regulation of inflammation and tumorigenesis in the colon.
Mutations in MEFV, the gene encoding pyrin in humans, are associated with the autoinflammatory disorder familial Mediterranean fever. Pyrin is an innate sensor that assembles into an inflammasome complex in response to Rho-modifying toxins, including Clostridium difficile toxins A and B. Cell death pathways have been shown to intersect with and modulate inflammasome activation, thereby affecting host defense. Using bone marrow-derived macrophages and a murine model of peritonitis, we show in this study that receptor-interacting protein kinase (RIPK) 3 impacts pyrin inflammasome activation independent of its role in necroptosis. RIPK3 was instead required for transcriptional upregulation of Mefv through negative control of the mechanistic target of rapamycin (mTOR) pathway and independent of alterations in MAPK and NF-κB signaling. RIPK3 did not affect pyrin dephosphorylation associated with inflammasome activation. We further demonstrate that inhibition of mTOR was sufficient to promote Mefv expression and pyrin inflammasome activation, highlighting the cross-talk between the mTOR pathway and regulation of the pyrin inflammasome. Our study reveals a novel interaction between molecules involved in cell death and the mTOR pathway to regulate the pyrin inflammasome, which can be harnessed for therapeutic interventions.
Abstract Epithelial response to injury is coordinated through an intricate interaction with neuronal and myeloid cells, however the signaling modules involved are not well understood. In humans, somatic mutations in Tet methylcytosine dioxygenase 2 (TET2), a DNA demethylase, are commonly observed during ageing in myeloid cells and known to modulate inflammatory responses. Using a mouse model that lacks TET2 in myeloid cells (Tet2 ΔLysM), we show that myeloid cells and sympathetic neurons form a signaling nexus that controls differentiation of enterochromaffin cells and serotonin production during colonic inflammation. Under physiological conditions, TET2 restricts IL-1β production by myeloid cells which in turn controls the intestinal sympathetic architecture. During inflammation, IL1R signaling limits sympathetic cues that drive differentiation of enterochromaffin cells through α1-adrenergic signaling. As a result, enterochromaffin differentiation and colitis progression in response to mucosal injury is attenuated in Tet2 ΔLysMmice. Further, protection from colitis in Tet2 ΔLysMmice is mediated by its catalytic activity, and dependent on sympathetic neurons and IL1R signaling. Adrenergic control of epithelial response and pro-colitic serotonin production is also evident under conditions of physiological stress that leads to increased colitis susceptibility. Overall, our study reveals a sympathetic-epithelial axis that controls the severity of colitis and is modulated by myeloid-derived IL-1β and physiological stress. Our findings may also explain why inflammatory bowel disease in the elderly, where TET2 mutations in myeloid cells are common, is less severe and suggests TET2 activity as an attractive target for IBD. Supported by the US National Institutes of Health (DK067180) to B.J, the University of Chicago's Center for Interdisciplinary Study of Inflammatory Intestinal Disorders (C-IID) Pilot & Feasibility Award (NIDDK P30 DK042086) to A.M. and D.S, Crohn’s and Colitis Foundation Career Development Award #964209 to A.M. and G.I. Research Foundation Associates Board Award to A.M. and D.S.
Abstract All nucleated cells express MHCI and IFN-gR. It is suggested that structural cells express MHCI to prevent NK-cell mediated cytotoxicity and allow deletion by CD8 +T cells upon intracellular perturbations, but a cell-specific function of antigen presentation via MHCI has not been explored. We show here that upon sensing IFN-g, colonic epithelial cells productively present pathogen and self-derived antigens to the cognate intra-epithelial T cells, which are critically located at the epithelial barrier. Antigen presentation by the epithelial cells confers ATPase expression in the cognate intra-epithelial T cells which limits the accumulation of extracellular ATP and consequent activation of the NLRP3 inflammasome in tissue macrophages. In contrast, antigen presentation by the tissue macrophages alongside inflammasome-associated IL-1a and IL-1b production promotes a pathogenic transformation of CD4 +T cells into GM-CSF-producing T cells in vivo, which underlies colitis and colorectal cancer. Supporting the relevance of these findings in humans, we show that the IBD-associated IFN-gR SNP leads to defective IFN-g signaling. Furthermore, decreased expression of IFN-gR or ATPase and increased expression of GM-CSF are associated with IBD that is resistant to the standard therapies, and reduced survival with colorectal cancer. Taken together, our study has unraveled a critical checkpoint requiring IFN-g sensing and antigen presentation by epithelial cells that control the development of pathogenic CD4 +T cell responses in vivo. Supported by the US National Institutes of Health (DK067180) to B.J, the University of Chicago's Center for Interdisciplinary Study of Inflammatory Intestinal Disorders (C-IID) Pilot & Feasibility Award (NIDDK P30 DK042086) to A.M. and D.S, Crohn’s and Colitis Foundation Career Development Award #964209 to A.M. and G.I. Research Foundation Associates Board Award to A.M. and D.S.
