Equally potent: Nlrp3 mutation in macrophages or neutrophils is sufficient to drive autoinflammation

Abstract

Gain-of-function mutation in NLRP3 is associated with a spectrum of autoinflammatory disorders including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal onset multisystem inflammatory disease, collectively known as cryopyrin-associated periodic syndrome (CAPS). However, the cell types mediating the pathogenesis of CAPS are not completely understood. Two studies in EMBO Reports now demonstrate that gain-of-function Nlrp3 mutation in either macrophages or neutrophils alone is sufficient to trigger systemic autoinflammation and lethality in mice.

Figure 1. Gain‐of‐function NLRP3 mutation in macrophage or neutrophils alone is sufficient to drive systemic inflammation

Gain‐of‐function Nlrp3 mutation in (A) macrophages or (B) neutrophils results in constitutive caspase‐1 activation, leading to enhanced cytokine processing (e.g., IL‐1β and IL‐18) and GSDMD cleavage. Constitutive NLRP3 activation in (A) macrophages or (B) neutrophils results in multi‐organ failure, defective hematopoiesis, systemic inflammation, and delayed growth and early lethality. These pathological effects can be partially suppressed by neutralizing IL‐1β and IL‐18. Global deletion of GSDMD rescues the auto‐inflammatory phenotype seen in in neutrophil‐restricted Nlrp3 mutant mice, while contribution of GSDMD in in macrophage‐restricted Nlrp3 mutant mice was not investigated.