Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes
. Activation of STING requires ...its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide
, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)-STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR-STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals
. The active bacterial TIR-STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD
hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.
Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of ...the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.
In the infarcted myocardium, activation of the inflammatory cascade clears the wound from dead cells, whereas stimulating matrix degradation and chamber dilation, thus contributing to the development ...of heart failure. IL-1 is critically involved in the postinfarction inflammatory reaction and mediates adverse dilative remodeling. We hypothesized that IL-1 may regulate postinfarction repair and remodeling through cell-specific actions on leukocytes and fibroblasts. Flow cytometry demonstrated that in mouse infarcts, early recruitment of proinflammatory Ly6C(hi) cells expressing IL-1R1, the signaling receptor for IL-1, was followed by infiltration with cells expressing the decoy receptor, IL-1R2. Increased expression of IL-1R2 may serve to terminate IL-1-driven inflammation after infarction. Loss of IL-1 signaling in IL-1R1 null mice globally attenuated leukocyte recruitment, reducing the number of infiltrating Ly6C(hi) and Ly6C(lo) cells. Nonmyeloid CD11b(-) cells harvested during the inflammatory phase of cardiac repair exhibited marked upregulation of chemokines and cytokines; their inflammatory activation was IL-1R1 dependent. Moreover, IL-1β attenuated TGF-β-induced contractile activity of fibroblasts populating collagen pads, attenuated α-smooth muscle actin expression, and stimulated matrix metalloproteinase synthesis in an IL-1R1-dependent manner. The effects of IL-1 on TGF-β responses in cardiac fibroblasts were not due to direct effects on Smad activation, but were associated with endoglin suppression and accentuated expression of bone morphogenetic protein and activin membrane-bound inhibitor, a negative regulator of TGF-β signaling. IL-1 may orchestrate fibroblast responses in the infarct; early stimulation of fibroblast IL-1R1 signaling during the inflammatory phase may prevent premature activation of a matrix-synthetic contractile phenotype until the wound is cleared, and the infarct microenvironment can support mesenchymal cell growth.
It was recently demonstrated that interleukin (IL)-23-driven IL-17-producing (ThIL-17) T cells mediate inflammatory pathology in certain autoimmune diseases. We show that the induction of ...antigen-specific ThIL-17 cells, but not T helper (Th)1 or Th2 cells, by immunization with antigens and adjuvants is abrogated in IL-1 receptor type I-deficient (IL-1RI(-/-)) mice. Furthermore, the incidence of experimental autoimmune encephalomyelitis (EAE) was significantly lower in IL-1RI(-/-) compared with wild-type mice, and this correlated with a failure to induce autoantigen-specific ThIL-17 cells, whereas induction of Th1 and Th2 responses was not substantially different. However, EAE was induced in IL-1RI(-/-) mice by adoptive transfer of autoantigen-specific cells from wild-type mice with EAE. IL-23 alone did not induce IL-17 production by T cells from IL-1RI(-/-) mice, and IL-23-induced IL-17 production was substantially enhanced by IL-1alpha or IL-1beta, even in the absence of T cell receptor stimulation. We demonstrate essential roles for phosphatidylinositol 3-kinase, nuclear factor kappaB, and novel protein kinase C isoforms in IL-1- and IL-23-mediated IL-17 production. Tumor necrosis factor alpha also synergized with IL-23 to enhance IL-17 production, and this was IL-1 dependent. Our findings demonstrate that IL-1 functions upstream of IL-17 to promote pathogenic ThIL-17 cells in EAE.
Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain ...unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related “sterile” inflammation in both periphery and brain independently of the noncanonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis. Consistent with the hypothesis that systemic low-grade inflammation promotes age-related degenerative changes, the deficient Nlrp3 inflammasome-mediated caspase-1 activity improved glycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer an innovative therapeutic strategy to lower Nlrp3 activity to delay multiple age-related chronic diseases.
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•Age-related DAMPs activate canonical Nlrp3 inflammasome without engaging caspase-11•Reduction in the Nlrp3 inflammasome activity reduces age-related inflammation•Ablation of Nlrp3 inflammasome slows age-related degenerative changes•IL-1 partakes in regulating age-related CNS inflammation and functional decline
IL-1 causes a marked increase in the degree of expansion of naïve and memory CD4 T cells in response to challenge with their cognate antigen. The response occurs when only specific CD4 T cells can ...respond to IL-1β, is not induced by a series of other cytokines and does not depend on IL-6 or CD-28. When WT cells are primed in IL-1R1⁻/⁻ recipients, IL-1 increases the proportion of cytokine-producing transgenic CD4 T cells, especially IL-17- and IL-4-producing cells, strikingly increases serum IgE levels and serum IgG1 levels. IL-1β enhances antigen-mediated expansion of in vitro primed Th1, Th2, and Th17 cells transferred to IL-1R1⁻/⁻ recipients. The IL-1 receptor antagonist diminished responses to antigen plus lipopolysaccharide (LPS) by almost equal to55%. These results indicate that IL-1β signaling in T cells markedly induces robust and durable primary and secondary CD4 responses.
The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for ...Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.
Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of ...cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice.
We obtained intestinal tissues from 92 patients with Crohn’s disease (CD), 48 patients with ulcerative colitis, and 26 patients without inflammatory bowel diseases (control individuals). Tissues were analyzed by histology to detect fibrosis and by immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R, and we studied intestinal tissues from Il1rl2–/– mice; colitis and fibrosis were induced in mice by repetitive administration of DSS or TNBS. Bone marrow cells were transplanted from Il1rl2–/– to irradiated wild-type mice and intestinal tissues were analyzed. Antibodies against IL36R were applied to mice with established chronic colitis and fibrosis and intestinal tissues were studied.
Mucosal and submucosal tissue from patients with CD or ulcerative colitis had higher levels of collagens, including type VI collagen, compared with tissue from control individuals. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed α-smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2–/– mice and mice given injections of an antibody against IL36R developed less severe colitis and fibrosis after administration of DSS or TNBS, but bone marrow cells from Il1rl2–/– mice did not prevent induction of colitis and fibrosis. Injection of antibodies against IL36R significantly reduced established fibrosis in mice with chronic intestinal inflammation.
We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD compared with control individuals. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R gene in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.
Progression of tuberculosis is tightly linked to a disordered immune balance, resulting in inability of the host to restrict intracellular bacterial replication and its subsequent dissemination. The ...immune response is mainly characterized by an orchestrated recruitment of inflammatory cells secreting cytokines. This response results from the activation of innate immunity receptors that trigger downstream intracellular signaling pathways involving adaptor proteins such as the TIR-containing adaptor protein (Tirap). In humans, resistance to tuberculosis is associated with a loss-of-function in Tirap. Here, we explore how genetic deficiency in Tirap impacts resistance to Mycobacterium tuberculosis (Mtb) infection in a mouse model and ex vivo. Interestingly, compared to wild type littermates, Tirap heterozygous mice were more resistant to Mtb infection. Upon investigation at the cellular level, we observed that mycobacteria were not able to replicate in Tirap-deficient macrophages compared to wild type counterparts. We next showed that Mtb infection induced Tirap expression which prevented phagosomal acidification and rupture. We further demonstrate that the Tirap-mediated anti-tuberculosis effect occurs through a Cish-dependent signaling pathway. Our findings provide new molecular evidence about how Mtb manipulates innate immune signaling to enable intracellular replication and survival of the pathogen, thus paving the way for host-directed approaches to treat tuberculosis.
Interleukin-1 (IL-1) signaling is important for multiple potentially pathogenic processes in the central nervous system (CNS), but the cell-type-specific roles of IL-1 signaling are unclear. We used ...a genetic knockin reporter system in mice to track and reciprocally delete or express IL-1 receptor 1 (IL-1R1) in specific cell types, including endothelial cells, ventricular cells, peripheral myeloid cells, microglia, astrocytes, and neurons. We found that endothelial IL-1R1 was necessary and sufficient for mediating sickness behavior and drove leukocyte recruitment to the CNS and impaired neurogenesis, whereas ventricular IL-1R1 was critical for monocyte recruitment to the CNS. Although microglia did not express IL-1R1, IL-1 stimulation of endothelial cells led to the induction of IL-1 in microglia. Together, these findings describe the structure and functions of the brain’s IL-1R1-expressing system and lay a foundation for the dissection and identification of IL-1R1 signaling pathways in the pathogenesis of CNS diseases.
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•Brain IL-1R1 is found in endothelial and ventricular cells, astrocytes, and DG neurons•Ventricular IL-1R1 regulates monocyte recruitment•Endothelial and ventricular IL-1R1 regulates IL-1-induced microglial activation•Endothelial IL-1R1 mediates sickness behavior, leukocyte recruitment, and neurogenesis
Liu et al. employ a genetic knockin reporter system in mice to track and reciprocally delete and/or express IL-1 receptor 1 (IL-1R1) in specific CNS cell types. They define cell-type-specific roles for IL-1 signaling, including an essential role for endothelial IL-1R1 in mediating sickness behavior, and provide a foundation for the dissection of IL-1R1 signaling pathways in the pathogenesis of CNS disease.
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