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Heme Oxygenase-1 Modulates Macrophage Polarization Through Endothelial Exosomal miR-184-3p and Reduces Sepsis-Induce
Wei Chen1, Yuan Zhang1,2,3, Jinkun Chen1
1Tianjin Nankai Hospital, Tianjin Medical University, Tianjin, 300100, People's Republic of China.
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.
Insights
Heme oxygenase-1 (HO-1) regulates macrophage polarization via pulmonary microvascular endothelial cell (PMVEC) exosomes, impacting sepsis-induced acute lung injury (ALI). HO-1 influences the miR-184-3p/Semaphorin 7A (Sema7a) pathway, modulating the M1/M2 macrophage ratio to mitigate lung inflammation.
Area of Science:
- Cell Biology
- Immunology
- Pathophysiology
Background:
- Sepsis-induced acute lung injury (ALI) involves pulmonary microvascular endothelial cells (PMVECs) and macrophage polarization.
- Heme oxygenase-1 (HO-1) exhibits protective functions in ALI, but its role in PMVEC exosome-mediated macrophage communication during sepsis is unclear.
Purpose of the Study:
- To investigate the mechanism by which HO-1 influences macrophage polarization through PMVEC-derived exosomes in sepsis-induced ALI.
- To elucidate the role of exosomal microRNAs (miRNAs) in HO-1-mediated intercellular communication between endothelial cells and macrophages.
Main Methods:
- Utilized HO-1 knockout mice and isolated exosomes from PMVECs.
- Determined differential miRNA expression in exosomes via sequencing.
- Employed an in vitro co-culture system of macrophages (MH-S cells) and PMVEC-derived exosomes, alongside in vivo analysis of pulmonary inflammation and macrophage polarization.
Main Results:
- miR-184-3p was significantly downregulated in exosomes from HO-1-overexpressing PMVECs (HP-exos).
- Overexpression of HO-1 led to decreased miR-184-3p, which negatively regulates Semaphorin 7A (Sema7a).
- This HO-1/miR-184-3p/Sema7a axis attenuated M1 macrophage polarization and promoted M2 polarization, thereby mitigating lung injury and inflammation.
Conclusions:
- HO-1 plays a critical role in modulating macrophage polarization via PMVEC exosomes during sepsis-induced ALI.
- The study identified a novel therapeutic pathway involving HO-1 regulating the miR-184-3p/Sema7a axis to control the M1/M2 macrophage ratio and alleviate lung inflammation.
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