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

INTRODUCTION

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.