Abstract
Neutrophil granule serine proteases contribute to immune responses through cleavage of microbial toxins and structural proteins. They induce tissue damage and modulate inflammation if levels exceed their inhibitors. Here, we show that the intracellular protease inhibitors Serpinb1a and Serpinb6a contribute to monocyte and neutrophil survival in steady-state and inflammatory settings by inhibiting cathepsin G (CatG). Importantly, we found that CatG efficiently cleaved gasdermin D (GSDMD) to generate the signature N-terminal domain GSDMD-p30 known to induce pyroptosis. Yet GSDMD deletion did not rescue neutrophil survival in Sb1a.Sb6a-/- mice. Furthermore, Sb1a.Sb6a-/- mice released high levels of pro-inflammatory cytokines upon endotoxin challenge invivo in a CatG-dependent manner. Canonical inflammasome activation in Sb1a.Sb6a-/- macrophages showed increased IL-1β release that was dependent on CatG and GSDMD. Together, our findings demonstrate that cytosolic serpins expressed in myeloid cells prevent cell death and regulate inflammatory responses by inhibiting CatG and alternative activation of GSDMD.
Highlights
Regulated forms of cell death are essential for the development of multicellular organisms and for their immune responses
regulated cell death (RCD) was synonymous with apoptosis, but it is recognized that RCD may involve necrosis resulting from distinct molecular pathways that have been principally defined as necroptosis and pyroptosis (Bliss-Moreau et al, 2017; Wallach et al, 2016)
Necroptosis occurs in many cell types and can be triggered by tumor necrosis factor-a (TNF-a) as well as other stimuli converging on receptor-interacting protein kinase-3 (RIPK3) (Cho et al, 2009; He et al, 2009; Zhang et al, 2009), which phosphorylates the pseudo-kinase mixed-lineage kinase-like protein (MLKL)
Summary
Regulated forms of cell death are essential for the development of multicellular organisms and for their immune responses. The most studied form of regulated cell death (RCD), is triggered by intrinsic or extrinsic cues transmitted to signaling routes converging on the proteolytic activation of executioner caspases. These apoptotic caspases cleave multiple protein targets in the nucleus, the cytoplasm, and the cytoskeleton but do not directly compromise the integrity of the plasma membrane (Taylor et al, 2008). RCD was synonymous with apoptosis, but it is recognized that RCD may involve necrosis resulting from distinct molecular pathways that have been principally defined as necroptosis and pyroptosis (Bliss-Moreau et al, 2017; Wallach et al, 2016) Such pathways may have evolved to trigger inflammation in response to potentially concealed infections and cytosolic microbes (Jorgensen et al, 2017; Miao et al, 2010). GSDMD-p30 assembles to form pores at the plasma membrane leading to cell lysis (Aglietti et al, 2016; Ding et al, 2016; Liu et al, 2016)
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