Abstract
Interleukin (IL)-37 is a member of the IL-1 family of cytokines. Although its broad anti-inflammatory properties are well described, the effects of IL-37 on inflammasome function remain poorly understood. Performing gene expression analyses, ASC oligomerization/speck assays and caspase-1 assays in bone marrow-derived macrophages (BMDM), and employing an in vivo endotoxemia model, we studied how IL-37 affects the expression and maturation of IL-1β and IL-18, inflammasome activation, and pyroptosis in detail. IL-37 inhibited IL-1β production by NLRP3 and AIM2 inflammasomes, and IL-18 production by the NLRP3 inflammasome. This inhibition was partially attributable to effects on gene expression: whereas IL-37 did not affect lipopolysaccharide (LPS)-induced mRNA expression of Il18 or inflammasome components, IL-37-transgenic BMDM displayed an up to 83% inhibition of baseline and LPS-stimulated Il1b compared to their wild-type counterparts. Importantly, we observed that IL-37 suppresses nigericin- and silica-induced ASC oligomerization/speck formation (a step in inflammasome activation and subsequent caspase-1 activation), and pyroptosis (−50%). In mice subjected to endotoxemia, IL-37 inhibited plasma IL-1β (−78% compared to wild-type animals) and IL-18 (−61%). Thus, our study adds suppression of inflammasome activity to the portfolio of anti-inflammatory pathways employed by IL-37, highlighting this cytokine as a potential tool for treating inflammasome-driven diseases.
Highlights
Interleukin (IL)-1β belongs to the IL-1 family, which further comprises the pro-inflammatory cytokines IL-1α, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ; and the anti-inflammatory family membersCells 2020, 9, 178; doi:10.3390/cells9010178 www.mdpi.com/journal/cellsIL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38 [1,2,3]
We investigated which inflammasomes are targeted by IL-37 and which steps of IL-1β production and inflammasome activation are affected by IL-37
IL-1β and IL-18 can be produced by different inflammasomes [7,12], and we decided to investigate the effect of IL-37 on IL-1β and IL-18 production by the NLRP3 and/or AIM2 inflammasomes
Summary
Interleukin (IL)-1β belongs to the IL-1 family, which further comprises the pro-inflammatory cytokines IL-1α, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ; and the anti-inflammatory family membersCells 2020, 9, 178; doi:10.3390/cells9010178 www.mdpi.com/journal/cellsIL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38 [1,2,3]. Interleukin (IL)-1β belongs to the IL-1 family, which further comprises the pro-inflammatory cytokines IL-1α, IL-18, IL-33, IL-36α, IL-36β, and IL-36γ; and the anti-inflammatory family members. IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38 [1,2,3]. IL-1β is a powerful inducer of inflammation [4,5]; its function must be tightly regulated. Production and release of IL-1β involves a two-step process. Therein, an inflammatory signal 1 initiates transcription and production of precursor (pro)-IL-1β and pro-IL-18. Examples for signal 1 events include cytokine signaling (for example, triggered by tumor necrosis factor (TNF)) [6], and activation of innate pattern-recognition receptors (PRR) by pathogen-associated molecular patterns, such as lipopolysaccharide (LPS) [7]. A danger signal (signal 2) subsequently activates
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