An inherited mutation in <i>NLRC4</i> causes autoinflammation in human and mice

TLDR

Autoinflammatory syndromes, such as familial cold autoinflammatory syndrome, cause sterile inflammation marked by rash, arthralgia, and fever triggered by cold, and the NLRC4 inflammasome is a key sensor of Gram‑negative bacteria. We discovered a missense NLRC4 mutation in FCAS patients that drives inflammasome assembly, elevates IL‑1β and IL‑17A from neutrophils, and in transgenic mice causes dermatitis and arthritis, establishing NLRC4 as a novel contributor to hereditary autoinflammation.

Abstract

Autoinflammatory syndromes cause sterile inflammation in the absence of any signs of autoimmune responses. Familial cold autoinflammatory syndrome (FCAS) is characterized by intermittent episodes of rash, arthralgia, and fever after exposure to cold stimuli. We have identified a missense mutation in the NLRC4 gene in patients with FCAS. NLRC4 has been known as a crucial sensor for several Gram-negative intracellular bacteria. The mutation in NLRC4 in FCAS patients promoted the formation of NLRC4-containing inflammasomes that cleave procaspase-1 and increase production of IL-1β. Transgenic mice that expressed mutant Nlrc4 under the invariant chain promoter developed dermatitis and arthritis. Inflammation within tissues depended on IL-1β–mediated production of IL-17A from neutrophils but not from T cells. Our findings reveal a previously unrecognized link between NLRC4 and a hereditary autoinflammatory disease and highlight the importance of NLRC4 not only in the innate immune response to bacterial infections but also in the genesis of inflammatory diseases.