Ankit Malik

IL-33 regulates the IgA-microbiota axis to restrain IL-1α–dependent colitis and tumorigenesis

Inflammatory bowel diseases (IBD) affect over 5 million individuals in the industrialized world, with an increasing incidence rate worldwide. IBD also predisposes affected individuals to development of colorectal cancer, which is a leading cause of cancer-related deaths in adults. Mutations in genes encoding molecules in the IL-33 signaling pathway are associated with colitis and colitis-associated cancer (CAC), but how IL-33 modulates gut homeostasis is unclear. Here, we have shown that Il33-deficient mice are highly susceptible to colitis and CAC. Mechanistically, we observed that IL-33 promoted IgA production from B cells, which is important for maintaining microbial homeostasis in the intestine. Il33-deficient mice developed a dysbiotic microbiota that was characterized by increased levels of mucolytic and colitogenic bacteria. In response to chemically induced colitis, this microbial landscape promoted the release of IL-1α, which acted as a critical driver of colitis and CAC. Consequently, reconstitution of symbiotic microbiota or IL-1α ablation markedly ameliorated colitis susceptibility in Il33-deficient animals. Our results demonstrate that IL-33 promotes IgA production to maintain gut microbial homoeostasis and restrain IL-1α-dependent colitis and CAC. This study therefore highlights modulation of IL-33, IgA, IL-1α, and the microbiota as a potential therapeutic approach in the treatment of IBD and CAC.

Nonhematopoietic β-Arrestin-1 Inhibits Inflammation in a Murine Model of Polymicrobial Sepsis

β-Arrestin-1 (βArr1), a scaffolding protein critical in G-protein coupled receptor desensitization has more recently been found to be important in the pathogenesis of various inflammatory diseases. We sought to understand the role of βArr1 in sepsis pathogenesis using a mouse model of polymicrobial sepsis. Although in previous studies we established that βArr1 deficiency protects mice from endotoxemia, here we demonstrate that the absence of βArr1 remarkably renders mice more susceptible to mortality in polymicrobial sepsis. In accordance with the mortality pattern, early production of inflammatory mediators was markedly enhanced in βArr1 knockout mice systemically and locally in various organs. In addition, enhanced inflammation in the heart was associated with increased NFκB activation. Compared to these effects, immune cell infiltration, thymic apoptosis, and immune suppression during polymicrobial sepsis were unaffected by a deficiency of βArr1. Additionally, enhanced inflammation and consequent higher mortality were not observed in heterozygous mice, suggesting that one allele of βArr1 was sufficient for this protective negative regulatory role. We further demonstrate that, unexpectedly, βArr1 in nonhematopoietic cells is critical and sufficient for inhibiting sepsis-induced inflammation, whereas hematopoietic βArr1 is likely redundant. Taken together, our results reveal a novel and previously unrecognized negative regulatory role of the nonhematopoietic βArr1 in sepsis-induced inflammation.

Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation.

Abstract:&bgr;-arrestin2 (&bgr;-arr2), identified as a scaffolding protein in G-protein-coupled receptor desensitization, is a negative regulator of inflammation in polymicrobial sepsis. In this study, we wanted to investigate the role of &bgr;-arr2 in intestinal inflammation, a site of persistent microbial stimulation. In the absence of &bgr;-arr2, mice exhibited greater extent of mucosal inflammation determined by cellular infiltration and expression of inflammatory mediators even under homeostatic conditions. Furthermore, &bgr;-arr2–deficient mice were more susceptible to dextran sulfate sodium–induced colitis as demonstrated by greater body weight loss, higher disease activity index, and shortened colon as compared with wild-type mice. We also show that T cells from &bgr;-arr2 knockout mice exhibit altered activation status under both basal and colitic conditions, implicating their involvement in disease induction. Further assessment of the role of &bgr;-arr2 in intrinsic T-cell differentiation confirmed its importance in T-cell polarization. Using the T-cell transfer model of colitis, we demonstrate that T-cell–specific &bgr;-arr2 is important in limiting colitic inflammation; however, it plays a paradoxical role in concurrent systemic wasting disease. Together, our study highlights a critical negative regulatory role of &bgr;-arr2 in intestinal inflammation and demonstrates a distinct role of T-cell-specific &bgr;-arr2 in systemic wasting disease.

Gene dosage-dependent negative regulatory role of β-arrestin-2 in polymicrobial infection-induced inflammation.

ABSTRACT 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.

Function and regulation of IL-1α in inflammatory diseases and cancer

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 (NLRs) 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.

Poly(I:C) Priming Exacerbates Cecal Ligation and Puncture-Induced Polymicrobial Sepsis in Mice

Sepsis continues to be a major healthcare issue with one of the highest mortality rates in intensive care units. Toll-like receptors are pattern recognition receptors that are intricately involved in the pathogenesis of sepsis. TLR3 is a major receptor for double-stranded RNA and is largely associated with immunity to viral infection. In this study, we examined the role of TLR3 priming in the immunopathology of sepsis using cecal-ligation and puncture (CLP) model of sepsis in mice. Mice injected with vehicle or poly(I:C) were subjected to sham or CLP surgery and various parameters of sepsis, including mortality, inflammation, and bacterial clearance were assessed. Poly(I:C) pre-treatment significantly enhanced mortality in mice subjected to CLP. Consistent with this, inflammatory cytokines including TNFα, IL-12p40, IFNγ, and MCP-1 were enhanced both systemically and locally in the poly(I:C)-treated group compared to the vehicle control. In addition, bacterial load was significantly higher in the poly(I:C)-treated septic mice. These changes were associated with reduced macrophage activation (but not neutrophils) in the peritoneal cavity of poly(I:C) pre-treated mice compared to vehicle pre-treatment. Together our results demonstrate that poly(I:C) priming in sepsis is likely to be detrimental to the host due to effects on systemic inflammatory cytokines and bacterial clearance.