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

Interleukin 1 (IL1) is a central driver of autoinflammatory disease, yet IL1 blockade often provides incomplete benefit in complex, neutrophil-driven conditions. Here we identify a licensing circuit in which common gamma chain cytokines provide a redundant signal required for maximal IL1 driven neutrophil inflammation. IL1 and gamma chain 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 IL1alpha driven neutrophil-dominant autoinflammation. Ablation of the shared gamma chain receptor markedly prolonged survival and attenuated pathology, whereas deletion of individual gamma chain 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 IL1, gamma chain, 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 gamma chain inputs enhance MEK/ERK-dependent inflammatory output, identify the gamma chain receptor as an in vivo disease-modifying node, and position MEK/ERK as a mechanistically grounded therapeutic target.