The NLRC4 Inflammasome

Abstract

15 years ago, the fundamental biology of an inflammatory signaling complex eventually dubbed "the inflammasome" began to unravel in chronologic parallel with the discovery that many inflammatory diseases were associated with its hyperactivity. Though the genetic origins of Familial Mediterranean Fever (FMF, caused my mutations in MEFV) were discovered first, it would take nearly two decades before the mechanistic connections to a PYRIN inflammasome were made. In the interim, the intensive study of the NLRP3 inflammasome, and the diseases associated with its hyperactivation, have largely dictated the paradigm of inflammasome composition and function. Despite impressive gains, focusing on NLRP3 left gaps in our understanding of inflammasome biology. Foremost among these gaps were how inflammasomes become activated and the connections between inflammasome structure and function. Fortunately, work in another inflammasome inducer, NLRC4, grew to fill those gaps. The current understanding of the NLRC4 inflammasome is perhaps the most comprehensive illustration of the inflammasome paradigm: trigger (e.g. cytosolic flagellin), sensor (NAIP), nucleator (NLRC4), adaptor (ASC), and effector (CASP1). Detailed work has also identified observations that challenge this paradigm. Simultaneously, the features unique to each inflammasome offer a lesson in contrast, providing perspectives on inflammasome activation, regulation, and function. In this review, we endeavor to highlight recent breakthroughs related to NLRC4 inflammasome structure and activation, important in vivo work in infection and systemic inflammation, and the characterization of a spectrum of human NLRC4-associated autoinflammatory diseases.

Keywords: Autoinflammation; Inflammasome; Inflammation; interleukin-18.

Figure

Structural, functional, and translational insights gleaned from the study of NLRC4 inflammasomes. Structural: NAIP proteins detect monomers of flagellin or Type III Secretion System (T3SS) needle or rod proteins and nucleate the oligomerization of NLRC4 to initiate inflammasome activation. Functional: NLRC4 inflammasomes present in macrophages, neutrophils, and Intestinal Epithelial Cells (IECs) mediate substrate cleavage via CASP1 or CASP8 to induce effector programs including release of inflammatory mediators and various cell death programs including Pore-Induced Intracellular Traps (PITs), and IEC expulsion. Translational: Gain-of-function (GOF) mutations clustering near NLRC4’s ADP-binding site have been associated with skin rash, enterocolitis, Macrophage Activation Syndrome, and chronically elevated IL-18. Figures adapted from Galan JE et al., Zhang L et al., Rauch I et al., Canna SW et al., and Kitamura A et al..