CXCR1 Depletion in Ly6C ⁺ cDC2 Alleviates Acute Lung Injury via Modulation of Th17/Treg Balance

Abstract Dendritic cells (DCs) play a critical role in the development of acute lung injury (ALI) / acute respiratory distress syndrome (ARDS), but the underlying mechanisms remain poorly understood, due to their heterogeneous phenotype and function. In this study, a novel DC subset is defined in mice, Ly6C⁺ cDC2, which corresponds to CD14⁺ cDC2 in humans. These subsets highly express C‐X‐C motif chemokine receptor 1 (Cxcr1) and exhibit pro‐inflammatory effects during ALI. Ex vivo, Ly6C⁺ cDC2s release higher levels of Il‐6 and Il‐1β, thereby promoting naïve T cells to differentiate into Th17 cells. Notably, Cxcr1 deficiency reduced the release of Il‐6 and Il‐1β from Ly6C⁺ cDC2s and shifted naïve T cells toward Treg differentiation, resulting in a decreased Th17/Treg ratio. In vivo, adoptive transfer of Ly6C⁺ cDC2s increased the Th17/Treg ratio in the lungs and spleens of LPS‐treated mice, exacerbating lung injury. Specific depletion of Cxcr1 in DCs significantly reduced the severity of ALI and mortality. Mechanistically, it is found that Cxcr1 regulates the expression of Il‐6 and Il‐1β in Ly6C⁺ cDC2s through the MEK1/ERK/NF‐κB pathway. Collectively, pro‐inflammatory Ly6C⁺ cDC2s are identified as key effector cells mediating the role of Cxcr1 signaling in modulating T cell differentiation, driving the progression of ALI.