Adventitial Niches, Complement and Inflammation in Pulmonary Vascular Disease: Current Status and Future Directions

Area of Science:

• Immunology
• Vascular Biology
• Complement System

Background:

• Inflammatory and autoimmune processes are implicated in pulmonary arterial hypertension (PAH) pathogenesis.
• Complement system dysregulation drives inflammation-mediated tissue injury in various diseases.
• The precise mechanisms initiating and sustaining inflammation in PAH remain unclear.

Purpose of the Study:

• To investigate the role of the complement system in pulmonary hypertension (PH) pathogenesis.
• To identify specific cellular and molecular players involved in complement-driven inflammation in PAH.
• To explore potential therapeutic targets within these inflammatory pathways.

Main Methods:

• Single-cell spatial transcriptomic analysis of human PAH lungs.
• Investigation of complement cascade activation, particularly the alternative pathway.
• Analysis of fibroblast- and CD8+ T cell-mediated complement activation.

Main Results:

• Complement cascade activation, especially the alternative pathway, drives proinflammatory responses in the pulmonary vasculature in PH.
• PAH lungs exhibit complement-rich adventitial fibroblasts, GZMK+ CD8 T cells, and activated macrophages forming proinflammatory niches.
• Intracellular and extracellular complement activation within fibroblasts, involving CFD and CFB, promotes mediator production and immune cell recruitment.

Conclusions:

• Local complement production by pulmonary artery adventitial fibroblasts and GZMK+ CD8+ T cells contributes to macrophage chemotaxis and activation.
• Complement-driven proinflammatory niches within PAH pulmonary arteries are key drivers of disease progression.
• These complement-mediated pathways represent promising therapeutic targets for PH.