Targeting Macrophage Crosstalk to PASMC by Blunting Inflammatory Phenotype Via SerpinB1 Protects Against
Jiajin Hao1,2, Guangyao Fang3, Xiuchuan Li2
1College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China (J.H., D.Y., Q.W., Y.Y., C.L.).
Background:
Perivascular macrophages play a significant role in the pathogenesis of hypoxia-induced pulmonary hypertension via crosstalk to pulmonary artery smooth muscle cells (PASMCs) to stimulate their proliferation and pulmonary vascular remodeling. However, whether hypoxia exposure of macrophages affects cellular crosstalk remains entirely unclear. This study aimed to decipher the effects of hypoxia on macrophages' crosstalk to PASMCs and elucidate the underlying molecular mechanisms.
Methods:
Conditioned medium obtained from bone marrow-derived macrophages under normoxia or hypoxia was transferred for hypoxic culture of primary mouse PASMCs, followed by RNA sequencing analysis. Myeloid-specific SerpinB1-overexpressing mice were generated to explore SerpinB1's role in macrophage inflammatory phenotype, PASMC proliferation, and pulmonary vascular remodeling.
Results:
Hypoxia-exposure of macrophages produced a conspicuous augmentation to the pro-proliferative effect of the conditioned medium on PASMCs. Hypoxia exposure aggravated macrophage inflammatory phenotype, as indicated by marked enrichment of multiple inflammatory pathways and elevated levels of inflammatory cytokines. SerpinB1 (serpin family B member 1) was identified as the key downstream mediator of hypoxia to regulate macrophage inflammatory phenotype because hypoxia induced its drastic downregulation and subsequent NLRP3 (NOD [nucleotide oligomerization domain]-, LRR [leucine-rich repeat]-, and PYD [pyrin domain]-containing protein 3)-independent inflammatory caspase-1 activation. Myeloid-specific overexpression of SerpinB1 largely blunted hypoxia-induced macrophage inflammatory phenotype and amplified the pro-proliferative effect on PASMCs. Myeloid SerpinB1-overexpressing mice exhibited lower right ventricular systolic pressure, milder right ventricular hypertrophy, and pulmonary vascular remodeling after chronic hypoxia exposure.
Conclusions:
Hypoxia exposure directly amplifies the pro-proliferative crosstalk of macrophages to PASMCs via downregulating SerpinB1 to induce caspase-1 activation and inflammatory phenotype. Targeting macrophage SerpinB1 may hold promise for treating pulmonary hypertension.
Insights
Hypoxia amplifies pulmonary hypertension by altering macrophage communication with smooth muscle cells. Downregulation of SerpinB1 in macrophages drives this process, suggesting SerpinB1 as a potential therapeutic target for pulmonary hypertension.
Area of Science:
- Cardiovascular Biology
- Immunology
- Cellular Signaling
Background:
- Perivascular macrophages contribute to pulmonary hypertension (PH) through crosstalk with pulmonary artery smooth muscle cells (PASMCs).
- The impact of hypoxia on macrophage-PASMC crosstalk and its underlying mechanisms remain largely unknown.
- Understanding this interaction is crucial for developing targeted PH therapies.
Purpose of the Study:
- To investigate how hypoxia affects macrophage crosstalk to PASMCs.
- To elucidate the molecular mechanisms driving hypoxia-induced changes in this crosstalk.
- To identify potential therapeutic targets for PH.
Main Methods:
- Primary mouse PASMCs were co-cultured with conditioned medium from macrophages exposed to normoxia or hypoxia.
- RNA sequencing was employed to analyze cellular responses.
- Myeloid-specific SerpinB1-overexpressing mice were utilized to assess SerpinB1's role in vivo.
Main Results:
- Hypoxia potentiated macrophage-induced PASMC proliferation and inflammatory phenotype.
- SerpinB1 (serpin family B member 1) was identified as a key mediator, downregulated by hypoxia.
- Hypoxia-induced SerpinB1 reduction led to caspase-1 activation and amplified pro-proliferative crosstalk.
- Overexpression of SerpinB1 in myeloid cells ameliorated hypoxia-induced PH phenotypes in mice.
Conclusions:
- Hypoxia exacerbates PH by downregulating macrophage SerpinB1, promoting inflammatory crosstalk with PASMCs via caspase-1 activation.
- Targeting macrophage SerpinB1 presents a promising therapeutic strategy for pulmonary hypertension.
- This study reveals a novel molecular pathway linking hypoxia, macrophage function, and PH pathogenesis.
