Roles of the Caspase-11 Non-Canonical Inflammasome in Rheumatic Diseases

Abstract

Inflammasomes are intracellular multiprotein complexes that activate inflammatory signaling pathways. Inflammasomes comprise two major classes: canonical inflammasomes, which were discovered first and are activated in response to a variety of pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and non-canonical inflammasomes, which were discovered recently and are only activated in response to intracellular lipopolysaccharide (LPS). Although a larger number of studies have successfully demonstrated that canonical inflammasomes, particularly the NLRP3 inflammasome, play roles in various rheumatic diseases, including rheumatoid arthritis (RA), infectious arthritis (IR), gouty arthritis (GA), osteoarthritis (OA), systemic lupus erythematosus (SLE), psoriatic arthritis (PA), ankylosing spondylitis (AS), and Sjögren's syndrome (SjS), the regulatory roles of non-canonical inflammasomes, such as mouse caspase-11 and human caspase-4 non-canonical inflammasomes, in these diseases are still largely unknown. Interestingly, an increasing number of studies have reported possible roles for non-canonical inflammasomes in the pathogenesis of various mouse models of rheumatic disease. This review comprehensively summarizes and discusses recent emerging studies demonstrating the regulatory roles of non-canonical inflammasomes, particularly focusing on the caspase-11 non-canonical inflammasome, in the pathogenesis and progression of various types of rheumatic diseases and provides new insights into strategies for developing potential therapeutics to prevent and treat rheumatic diseases as well as associated diseases by targeting non-canonical inflammasomes.

Keywords: caspase-11; caspase-4; inflammasome; non-canonical inflammasome; rheumatic disease.

Figure 1

Structure of caspase-11 non-canonical inflammasome and caspase-11 non-canonical inflammasome-activated inflammatory signaling pathways. (A) Structural comparison of mouse caspase-11, human caspase-4, and caspase-5. (B) LPS originating from Gram-negative bacteria enters the cells, and then caspase-11 senses the intracellular LPS by direct interaction to form LPS-caspase-11 complexes, leading to the generation of caspase-11 non-canonical inflammasome by oligomerization of the LPS-caspase-11 complexes and the activation of caspase-11 non-canonical inflammasome by autoproteolysis. Activated caspase-11 non-canonical inflammasome induces GSDMD proteolysis and GSDMD pore formation, resulting in pyroptosis of the cells. Activated caspase-11 non-canonical inflammasome also induces proteolytic maturation of pro-IL-1β and pro-IL-18, and the IL-1b and IL-18 are secreted from the cells through the GSDMD pores.

Figure 2

Regulatory roles of mouse caspase-11 and human caspase-4 non-canonical inflammasomes in RA pathogenesis in RASFs and RA mouse models.

Figure 3

Regulatory roles of mouse caspase-11 non-canonical inflammasomes in GA pathogenesis in an MSU-induced GA mouse model.

Figure 4

Regulatory roles of mouse caspase-11 and human caspase-4 non-canonical inflammasomes in OA pathogenesis in human OA patients and OA mouse models.

Figure 5

Regulatory roles of mouse caspase-11 non-canonical inflammasomes in SLE pathogenesis in lupus mouse models.

Figure 6

Regulatory roles of mouse caspase-11 non-canonical inflammasomes in SjS pathogenesis in SjS mouse models.