Regulatory Roles of the Caspase-11 Non-Canonical Inflammasome in Inflammatory Diseases

Abstract

Inflammation is an immune response mediated by innate immune cells of tissues, against invading microbes and cellular stress. The hallmark of inflammatory responses is the activation of inflammasomes - multiprotein oligomers comprising intracellular pattern recognition receptors and inflammatory effectors - such as ASC and pro-cysteine-aspartic protease (pro-caspase)-1. Inflammasomes can be classified as canonical or non-canonical, and their activation in response to various ligands commonly induces caspase-1 activation and gasdermin D (GSDMD) processing, leading to caspase-1-mediated maturation and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and GSDMD-mediated pyroptosis through pore generation in cell membranes. Although inflammation protects the host from harmful stimuli, chronic inflammation is a critical risk factor for inflammatory diseases, and several studies have investigated the role of canonical inflammasomes in inflammatory responses and diseases, with emerging studies focusing on the role of non-canonical inflammasomes. This review discusses recent studies on the regulatory roles of the caspase-11 non-canonical inflammasome in the pathogenesis of inflammatory diseases. Additionally, it provides an insight into the development of novel therapeutics based on targeting caspase-11 non-canonical inflammasome and its downstream effectors to prevent and treat human inflammatory conditions.

Keywords: Caspase-11; Inflammasome; Inflammatory diseases; Inflammatory responses; Non-canonical.

Figure 1. Activation of caspase-4/5/11 non-canonical inflammasomes. (A) LPS-harboring OMVs derived from gram-negative bacteria are endocytosed into the host cells, and (B) intracellular LPS directly interacts with mouse caspase-11 or human caspase-4/5 (caspase-4/5/11) through the caspase-4/5/11 CARDs and the lipid A moiety of intracellular LPS, (C) leading to the oligomerization of LPS-caspase-4/5/11 complexes to be activated. (D) Activated caspase 4/5/11 non-canonical inflammasomes cleave the linker loop of GSDMD at Asp276 residue to produce N- and C-terminal GSDMD fragments, and (E) the GSDMD N-terminal fragments generate GSDMD pores in the cell membranes by oligomerization, (F) resulting in cell swelling and rupture, known as pyroptosis. (G) Activated caspase 4/5/11 non-canonical inflammasomes also induce NLRP3 canonical inflammasome activation via an unknown mechanism, (H) leading to the proteolysis and activation of pro-caspase-1 to form active caspase-1 dimers. (I) Active caspase-1 dimer subsequently induces proteolysis and maturation of the inactive pro-inflammatory cytokines pro-IL-1β and pro-IL-18 to active IL-1β and IL-18, and (J) these active IL-1β and IL-18 are secreted through the GSDMD pores.

N, GSDMD N-terminal fragment; C, GSDMD C-terminal fragment; PYD, pyrin domain; NACHT, nucleotide-binding and oligomerization domain; Asp276, aspartic acid 276 residue.