An inherited mutation in NLRC4 causes autoinflammation in human and mice

Kitamura et al. identify NLRC4 as causing familial cold autoinflammatory syndrome using whole exome sequencing on a family with multiple affected family members. They identify a mutation in the NOD domain and show that the mutant protein increases Nlrc4 oligomerization and is associated with increased IL-1β. Transgenic mice with the same NLRC4 mutation are shown to develop a similar FCAS-like syndrome.
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.