Heme Oxygenase-1 Modulates Macrophage Polarization Through Endothelial Exosomal miR-184-3p and Reduces Sepsis-Induce Lung Injury

Wei Chen,1,* Yuan Zhang,1– 3,* Jinkun Chen,1,* Shuan Dong,1– 3 Xiaoyang Wu,1 Ya Wu,1 Zhuo Du,1 Yibo Yang,1 Lirong Gong,1– 3 Jianbo Yu1– 3 1Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, 300100, People’s Republic of China; 2Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin, 300100, People’s Republic of China; 3Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin, 300100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianbo Yu; Lirong Gong, Tianjin Nankai Hospital, Tianjin Medical University, 6 Changjiang Road, Nankai District, Tianjin, 300100, People’s Republic of China, Email 30717008@nankai.edu.cn; soundglr@163.comIntroduction: Pulmonary microvascular endothelial cells (PMVECs) are notably implicated in the pathogenesis of sepsis-induced lung injury. Exosomes derived from PMVECs facilitate intercellular communication among various cell types, especially crosstalk with macrophages. Heme oxygenase-1 (HO-1), an early stress-responsive enzyme with inherent protective functions, has been implicated in acute lung injury (ALI) mitigation. But research on the mechanism of HO-1 in macrophage polarization via PMVEC exosomes in sepsis-induced lung injury is lacking.Methods: To investigate the role of HO-1 in the interaction between endothelial cells and macrophages, HO-1 knockout mouse model were established. Exosomes from PMVECs were isolated, and differential expression of microRNA (miRNA) was determined by sequencing. An in vitro co-culture system involving Murine Alveolar Macrophage Cell Line (MH-S cells) and HO-1/ PMVECs-derived exosomes (HP-exos) was used to investigate the underlying mechanisms. To further verify the involvement of HO-1 in intercellular communication through exosomal miRNA in vivo, the level of pulmonary inflammation was evaluated, and the polarization of pulmonary macrophages was analyzed.Results: The results showed that miR-184-3p was significantly downregulated in HP-exos, and supplementation of miR-184-3p enhanced the polarization of M1 macrophages, thus intensifying lung inflammation. HO-1 regulates the polarization of macrophages by regulating endothelial exosomes. Overexpression of HO-1 downregulates miR-184-3p, which negatively regulates Semaphorin 7A (Sema7a), which attenuated M1 type macrophages (M1) polarization and augmented M2 type macrophages (M2) polarization, thereby partially mitigating lung injury and inflammation.Conclusion: Collectively, we elucidated a novel potential therapeutic mechanism that HO-1 alleviate inflammation by modulating the M1/M2 ratio in sepsis-induced ALI by regulating miR-184-3p/Sema7a expression. Keywords: sepsis, acute lung injury, macrophage polarization, exosome, MiRNA