Deficiency of HIF-1α in myeloid cells protects Escherichia coli or LPS-induced acute lung injury

Abstract

Summary Background Deficiency of hypoxia-induced factor-1α (HIF-1α) in macrophages reduced lipopolysaccharide (LPS)-induced mortality; however, whether HIF-1α expression in myeloid cells would contribute to the development of Escherichia coli (E. coli) or LPS-induced acute lung injury (ALI) is less investigated. Aim To test whether deletion of Hif1α in myeloid cells affects E. coli or LPS-induced ALI and to elicit the underlying mechanisms. Design Laboratory study. Methods We intratracheally challenged Hif1α fl/fl and Hif1α fl/fl LysM Cre mice with E. coli or LPS to analyze lung and spleen inflammatory responses. Flow cytometry was used to analyze the changes of α7 nAChR + CD11b + cells in the lung and spleen. Double knockout of Chrna7 and Itgam mice were used to examine expression of HIF-1α during E. coli lung infection. Vagotomy was performed to demonstrate the role of vagus nerve in mediating protective effects of deletion of Hif1α in myeloid cells on LPS-induced ALI. Results Deletion of Hif1α in myeloid cells could reduce lung edema, inflammatory cell infiltration, and lung and BAL inflammatory cytokines in E. coli-induced ALI. Flow cytometric analysis revealed that α7 nAChR + CD11b + cells in the lung and spleen were markedly increased in E. coli-challenged Hif1α fl/fl LysM Cre mice compared with E. coli-challenged Hif1α fl/fl mice. Double knockout of Chrna7 and Itgam increased HIF-1α expression in lung and spleen cells during lung E. coli infection. Vagotomy abolished the protective effect of deletion of Hif1α in myeloid cells on LPS-induced ALI. Conclusion Deletion of Hif1α in myeloid cells could protect mice from lung injury depending on α7 nAChR + CD11b + cells and innervation of vagal circuits.