Ly6C+ cDC2-specific CXCR1 defects mitigate acute lung injury by suppressing the Th17/Treg imbalance via MEK1/ERK signaling downregulation.

Acute lung injury (ALI) poses a life-threatening risk due to uncontrolled inflammatory responses, including cytokine dysregulation and Th17/Treg imbalance. The specific role of dendritic cells (DC) in Th17/Treg differentiation during ALI is not fully understood, given their diverse subtypes and unidentified regulatory molecules. Our study revealed that mice with DC-specific deletion of C-X-C motif chemokine receptor 1 (CXCR1) exhibited improved outcomes in ALI. We observed a significant expansion of Treg cells in mice with DC-specific deletion of CXCR1 via single-cell RNA sequencing. Additional investigations substantiated that the primary consequence of CXCR1 deficiency within LY6C⁺ cDC2, was reduction in the generation of interleukin-6 (IL-6) and interleukin-1β (IL-1β), which favors the conversion of Treg cells over Th17 cells. Adoptive transfer of CXCR1-deficient Ly6C⁺ cDC2 significantly reduced the Th17/Treg ratio in the lungs and spleens of recipient mice, thereby alleviating ALI. Mechanistically, we identified that CXCR1 activated the MEK1/ERK signaling pathway to initiate NF-κB-dependent inflammatory responses, thereby regulating the transcription and production of IL-6 and IL-1β. Therefore, CXCR1 defects specified by LY6C⁺ cDC2 is essential for converting its inflammatory phenotype and suppressing the Th17/Treg imbalance, dampening the ALI development.