Mucosal Immunol. 2025 Mar 28:S1933-0219(25)00031-5. doi: 10.1016/j.mucimm.2025.03.005. Online ahead of print.
ABSTRACT
Heatstroke (HS) is typically considered a sepsis-like syndrome caused by hyperthermia, often accompanied by multiple organ dysfunctions (MODS). To explore the mechanisms of MODS, we established a mouse model of HS by exposing mice to a hyperthermic and high-humidity environment. Then, we utilized single-cell RNA sequencing (scRNA-seq) to depict the cellular landscape of HS mice lung tissue and liver tissue. We found that the enhancement of neutrophil infiltration mediated by the “Cxcr2-Cxcl2″ receptor-ligand pair is a prominent feature of HS-induced lung injury. By effectively suppressing the recruitment of neutrophils in HS-induced lung injury, the application of Cxcr2 inhibitor held positive implications for improving HS-induced lung injury. In addition to the chemotactic effect of immune cells on neutrophils, we identified a subcluster of fibroblasts labeled as Col14a1+, which possessed notable chemotactic factor-secretion characteristics and likely exerted a role in the early stages of neutrophil infiltration. Furthermore, our study unveiled significant heterogeneity among neutrophils within the HS-induced lung injury. Particularly, Cd177 + neutrophils exhibited a dominant presence, characterized by heightened pro-inflammatory responses and oxidative stress. In heatstroke-induced liver injury, neutrophils exhibited similar heterogeneous characteristics. Cd177 + neutrophils exhibited an enhanced ability to produce neutrophil extracellular traps (NETs) while lowering the levels of NETs can significantly improve heatstroke-induced lung and liver injury. Additionally, our study identified Cebpe as a key transcriptional regulatory factor in Cd177 + neutrophil differentiation. Knockdown of the expression of Cebpe can suppress the Cd177 + neutrophil differentiation and decrease the expression levels of NETs. Our research indicated a common heterogeneity in neutrophils during MODS in HS. Cd177 + neutrophils contributed to organ damage in HS, and Cebpe may serve as a crucial intervention target in the treatment of HS.
PMID:40158777 | DOI:10.1016/j.mucimm.2025.03.005