Redundant γc cytokines license IL-1-driven neutrophil inflammation through MEK/ERK convergence.

Interleukin-1 (IL-1) is a central driver of autoinflammatory disease, yet IL-1 blockade often provides incomplete benefit in complex, neutrophil-driven conditions. Here we identify a licensing circuit in which common γ-chain (γc) cytokines provide a redundant signal required for maximal IL-1-driven neutrophil inflammation. IL-1 and γc cytokines synergize to drive inflammatory cytokine production exceeding either stimulus alone, and these signals engage the MEK/ERK pathway, an effect substantially suppressed by pharmacological MEK inhibition. We validated this circuit in vivo in a mouse model of IL-1α-driven neutrophil-dominant autoinflammation. Ablation of the shared γc receptor markedly prolonged survival and attenuated pathology, whereas deletion of individual γc cytokine pathways had no major effect-demonstrating in vivo necessity and functional redundancy. Analysis of public phospho-proteomic and transcriptomic datasets confirms MEK/ERK as a conserved neutrophil response to diverse inflammatory stimuli and coordinated IL-1, γc, and MEK/ERK activation in neutrophils from patients with systemic juvenile idiopathic arthritis (sJIA) and in lesional skin from hidradenitis suppurativa. Together, these findings define a signaling architecture in which redundant γc inputs enhance MEK/ERK-dependent inflammatory output, identify the γc receptor as an in vivo disease-modifying node, and position MEK/ERK as a mechanistically grounded therapeutic target.