CXCR1 Depletion in Ly6C

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.