Abstract
Since IL-37 transgenic mice possesses broad anti-inflammatory properties, we assessed whether recombinant IL-37 affects inflammation in a murine model of invasive pulmonary aspergillosis. Recombinant human IL-37 was injected intraperitoneally into mice prior to infection and the effects on lung inflammation and inflammasome activation were evaluated. IL-37 markedly reduced NLRP3-dependent neutrophil recruitment and steady state mRNA levels of IL-1β production and mitigated lung inflammation and damage in a relevant clinical model, namely aspergillosis in mice with cystic fibrosis. The anti-inflammatory activity of IL-37 requires the IL-1 family decoy receptor TIR-8/SIGIRR. Thus, by preventing activation of the NLRP3 inflammasome and reducing IL-1β secretion, IL-37 functions as a broad spectrum inhibitor of the innate response to infection-mediated inflammation, and could be considered to be therapeutic in reducing the pulmonary damage due to non-resolving Aspergillus infection and disease.
Highlights
IL-37 is a member of the IL-1 family of ligands discovered by computational cloning and previously termed IL-1 family member 7 [1]
We observed that IL-37 limits inflammation and disease severity in murine invasive aspergillosis, an infection model in which cytokines of the IL-1 family have important roles
Given that IL-1R1-deficient or caspase 1-deficient mice are resistant to lung inflammation during infection and that IL-1 signaling could drive the differentiation of antifungal inflammatory Th17 cells, the pro-inflammatory properties of IL 1-induced inflammation in aspergillosis is potentially dangerous for the host
Summary
IL-37 is a member of the IL-1 family of ligands discovered by computational cloning and previously termed IL-1 family member 7 [1]. Five different splice variants of IL-37 have been described [2,3]. The major splice variant is IL-37b [4] and, similar to most members of the IL-1 family, lacks a clear signal peptide. The precursor form is a ,30-kDa molecular mass protein that shares critical amino acid residues with IL-18 [5]. IL-37 translocates to the nucleus and reduces LPS-induced cytokines. The nuclear translocation of IL-37 requires caspase-1 activity as assessed by caspase-1 inhibitors [8] or by mutation of the caspase-1 recognition aspartic acid in the IL-37 precursor [9]. IL-37 exerts anti-inflammatory effects by suppressing innate immune responses through attenuating the production of inflammatory cytokines induced by TLR agonists, IL-1 and tumor necrosis factor (TNF) [8,10]
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