Intracellular Interleukin-1 Receptor 2 Binding Prevents Cleavage and Activity of Interleukin-1α, Controlling Necrosis-Induced Sterile Inflammation

Abstract

SummaryNecrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

“…Also, our observed defects in IL-1α production in calpain KO mice may lead to defects in neutrophil recruitment given recent studies of IL-1α function in promoting neutrophil recruitment to the peritoneum during sterile inflammation [25]. Although both p33 and p17 forms were detected in PLF, a more recent study demonstrates that the calpain-cleaved form of IL-1α (p17) is much more active than p33 in eliciting neutrophils [41]. between WT and KO mice by FACS staining of Gr-1 hi /CD11b hi cells in the peritoneum.…”

“…Although release of both p33 and p17 were detected during sterile inflammation, the exact contributions of these cytokines to IL-1R1 signaling was not reported [25]. However, Clarke et al recently demonstrated that cleavage of p33 to p17 by calpains enhances IL-1R1 binding and elicits neutrophils more efficiently than p33 [41]. They also report a soluble receptor (IL-1R2) that prevents cleavage of p33 until inflammasome activation leads to Caspase-1-mediated proteolysis of IL-1R2, thus allowing subsequent cleavage of p33 by calpains [41].…”

“…However, Clarke et al recently demonstrated that cleavage of p33 to p17 by calpains enhances IL-1R1 binding and elicits neutrophils more efficiently than p33 [41]. They also report a soluble receptor (IL-1R2) that prevents cleavage of p33 until inflammasome activation leads to Caspase-1-mediated proteolysis of IL-1R2, thus allowing subsequent cleavage of p33 by calpains [41]. Our results provide further support for calpain-dependent IL-1α production and neutrophil recruitment during acute bacterial infection in vivo.…”

Pneumolysin-Dependent Calpain Activation and Interleukin-1α Secretion in Macrophages Infected with Streptococcus pneumoniae

“…It was reported previously that several inflammasome activators induce the maturation and secretion of IL-1␣ in a manner dependent on inflammasome components, including ASC (apoptosis-associated speck-like protein containing a CARD [caspase activation and recruitment domain]) and caspase-1 (30)(31)(32)(33). We previously reported that in S. pneumoniae-infected macrophages, the AIM2 and NLRP3 inflammasomes play a critical role in caspase-1 activation and the subsequent processing and secretion of IL-18 and IL-1␤ (11).…”

“…Gross Role of Pneumolysin in IL-1␣ Secretion Infection and Immunity contributed to the processing and secretion of IL-1␣ independently of its proteolytic activity, but IL-1␣ secretion was not universally inflammasome dependent, as several particulate NLRP3 activators induced it in the absence of NLRP3, caspase-1, or ASC (30). Zheng et al proposed that IL-1 receptor 2 (IL-1R2) interacts with pro-IL-1␣, which prevents IL-1␣ maturation by calpain, and that caspase-1 cleaves IL-1R2 to resolve this inhibition (33). However, Dewamitta et al reported that the maturation of IL-1␣ in macrophages infected by Listeria monocytogenes is independent of caspase-1 and ASC (26).…”