Macrophages respond to microbial ligands and various noxious cues by initiating an inflammatory response aimed at eliminating the original pathogenic insult. Transition of macrophages from a proinflammatory state to a reparative state, however, is vital for resolution of inflammation and return to homeostasis. The molecular players governing this transition remain poorly defined. Here, we find that the reparative macrophage transition is dictated by B-cell adapter for PI3K (BCAP). Mice harboring a macrophage-specific deletion of BCAP fail to recover from and succumb to dextran sulfate sodium-induced colitis due to prolonged intestinal inflammation and impaired tissue repair. Following microbial stimulation, gene expression in WT macrophages switches from an early inflammatory signature to a late reparative signature, a process that is hampered in BCAP-deficient macrophages. We find that absence of BCAP hinders inactivation of FOXO1 and GSK3β, which contributes to their enhanced inflammatory state. BCAP deficiency also results in defective aerobic glycolysis and reduced lactate production. This translates into reduced histone lactylation and decreased expression of reparative macrophage genes. Thus, our results reveal BCAP to be a critical cell-intrinsic switch that regulates transition of inflammatory macrophages to reparative macrophages by imprinting epigenetic changes.
The cytokine interleukin-1β (IL-1β) is a key mediator of anti-microbial immunity as well as autoimmune inflammation. Production of IL-1β requires transcription by innate immune receptor signaling and maturational cleavage by inflammasomes. Whether this mechanism applies to IL-1β production seen in T cell-driven autoimmune diseases remains unclear. Here, we describe an inflammasome-independent pathway of IL-1β production that was triggered upon cognate interactions between effector CD4 + T cells and mononuclear phagocytes (MPs). The cytokine TNF produced by activated CD4 + T cells engaged its receptor TNFR on MPs, leading to pro-IL-1β synthesis. Membrane-bound FasL, expressed by CD4 + T cells, activated death receptor Fas signaling in MPs resulting in caspase-8-dependent pro-IL-1β cleavage. The T cell-instructed IL-1β Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Intestinal epithelial cells (IECs) provide a critical first line of defense against microbes through barrier function, production of antimicrobial peptides (AMPs), secretion of cytokines, and recruitment of inflammatory cells. Whether single or multiple upstream cues regulate this diverse set of responses from IECs is not clear. Here we discover an unexpected role for Interleukin-1 Receptor (IL-1R) signaling in IECs in regulating intestinal homeostasis and inflammation. Specifically, absence of IL-1R in epithelial cells abrogates a homeostatic anti-microbial program including production of AMPs. Although IL-1R signaling alone is not sufficient to drive the AMP gene induction in IECs, the IL-22-driven anti-microbial program requires synergistic IL-1R signaling. Mechanistically, IL-1R signaling results in enhancement and temporal stabilization of STAT3 phosphorylation downstream of IL-22R. Thus, we reveal an unexpected cooperation between IL-1R and IL-22R in directly regulating an intestinal anti-microbial program. In contrast, absence of IL-1R in IECs protects mice from chemically-induced acute intestinal inflammation suggesting that IEC specific IL-1R signaling contributes to inflammation and pathology. We find that IL-1R signaling directly induces expression of chemokines as well as genes involved in the production of reactive oxygen species in IECs, a process that likely evolved to protect against enteric pathogens. Our findings establish a critical role for IEC specific IL-1R signaling in both steady state anti-microbial gene induction as well as intestinal inflammation. Further studies are likely to reveal potential targets for developing therapies against Crohn’s Disease and Ulcerative Colitis.
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