Complement-containing small extracellular vesicles from adventitial fibroblasts induce proinflammatory and metabolic...

Area of Science:

• Cardiology
• Immunology
• Cell Biology

Background:

• Pulmonary hypertension (PH) involves inflammation driven by fibroblasts and complement.
• Small extracellular vesicles (sEVs) are implicated in intercellular communication in disease.

Purpose of the Study:

• To investigate the role of fibroblast-derived sEVs in mediating complement-dependent macrophage activation in PH.
• To identify specific molecular mechanisms by which sEVs contribute to PH pathogenesis.

Main Methods:

• Isolation and characterization of adventitial fibroblasts and their secreted sEVs from PH and control calves.
• In vitro studies using bone marrow-derived macrophages (BMDMs) exposed to sEVs.
• Proteomic and metabolomic analyses of sEVs.
• Pharmacological and genetic inhibition of sEV release and complement component C3.

Main Results:

• PH fibroblasts released more sEVs than control fibroblasts.
• sEVs from PH fibroblasts (PH-Fib-sEVs) induced greater proinflammatory cytokine and metabolic gene expression in BMDMs.
• PH-Fib-sEVs were enriched in complement and coagulation factors, including C3.
• Inhibition of sEV release or C3 significantly attenuated macrophage proinflammatory activation.

Conclusions:

• Fibroblast-derived sEVs are critical mediators of complement-dependent inflammation in pulmonary hypertension.
• PH-Fib-sEVs promote a proglycolytic and proinflammatory phenotype in macrophages.
• Targeting fibroblast-derived sEVs or the complement pathway presents a potential therapeutic strategy for PH.