Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses

Abstract

Different modes of cell death regulate immunity. Whereas necrotic (necroptotic, pyroptotic) cell death triggers inflammation, apoptosis contributes to its resolution. Interleukin-1 (IL-1) family cytokines are key players in this interaction. A number of IL-1 family cytokines are produced by necrotic cells to induce sterile inflammation. However, release of IL-1 family proteins from apoptotic cells to regulate inflammation was not described. Here we show that IL-38, a poorly characterized IL-1 family cytokine, is produced selectively by human apoptotic cells to limit inflammation. Depletion of IL-38 in apoptotic cells provoked enhanced IL-6 and IL-8 levels and AP1 activation in co-cultured human primary macrophages, subsequently inducing Th17 cell expansion at the expense of IL-10-producing T cells. IL-38 was N-terminally processed in apoptotic cells to generate a mature cytokine with distinct properties. Both full-length and truncated IL-38 bound to X-linked interleukin-1 receptor accessory protein-like 1 (IL1RAPL1). However, whereas the IL-38 precursor induced an increase in IL-6 production by human macrophages, truncated IL-38 reduced IL-6 production by attenuating the JNK/AP1 pathway downstream of IL1RAPL1. In conclusion, we identified a mechanism of apoptotic cell-dependent immune regulation requiring IL-38 processing and secretion, which might be relevant in resolution of inflammation, autoimmunity, and cancer.

IL-38 overexpression induces anti-inflammatory effects in mice arthritis models and in human macrophages in vitro

“…These effects could indirectly influence the expression of Th17 cytokines (figure 6E). Overall, these results are in accordance with previous studies showing that IL-38 restricts macrophage-dependent generation of Th17 cells2 and that TNFα and IL-6 are not regulated as IL-1β in macrophages 27. The fact that IL-38 overexpression does not reduce IL-6 expression in CIA mice could be explained by the numerous different cell types that produce this pleiotropic cytokine in vivo, some of which being possibly not responsive to IL-38.…”

“…IL-38 is a 17–18 kDa weight protein devoid of signal peptide or caspase-1 cleavage site. It was shown that apoptotic cells were able to produce a mature, truncated form of IL-38, but the exact cleavage site and the protease responsible for this maturation are not yet identified 2. Recently we have shown that IL-38 is expressed by keratinocytes, synovial fibroblast from patients with rheumatoid arthritis (RA), as well as by human monocytes and type I macrophages (M1) polarised in vitro 3.…”

“…IL-38 could bind three different receptor chains, IL-1R1,1 IL-36R15 and the orphan receptor IL-1RAPL1 2. In peripheral blood mononuclear cells (PBMCs) stimulated with IL-36γ, IL-38 decreases IL-8 expression.…”

“…PBMCs from healthy donors treated with siRNA targeting IL-38 produced significantly more proinflammatory mediators after stimulation with toll-like receptors 7 and 9 ligands 9. IL-38 depletion also exacerbated the expression of IL-6 and IL-8 in cultured macrophages 2. Interestingly, full length recombinant IL-38 induced IL-6 production by macrophages, whereas truncated IL-38 decreased IL-6 expression after IL-1RAPL1 binding 2…”

Cytokines in the pathogenesis of rheumatoid arthritis: new players and therapeutic targets

“…IL-38 is selectively secreted by human apoptotic cells to counteract inflammation. The depletion of IL-38 in apoptotic cells leads to an increase of pro-inflammatory cytokine release by macrophages and to the subsequent expansion of Th17-cell at expense of IL-10-producing T cells [46]. Interestingly, in this study, full length recombinant IL-38 induced IL-6 production by macrophages, whereas truncated IL-38 decreased IL-6 expression after X-linked interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1) binding.…”