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

There is strong evidence supporting inflammatory and autoimmune processes in the pathogenesis of pulmonary arterial hypertension (PAH), although the initiating and disease-sustaining mechanisms remain unclear. Studies in arthritis, kidney disease, and cancer have demonstrated that dysregulation of the complement system can drive inflammation-mediated tissue injury. We have shown that activation of the complement cascade, particularly the alternative pathway, within the pulmonary vasculature is a key driver of proinflammatory responses in pulmonary hypertension (PH). Single-cell spatial transcriptomic analysis of PAH lungs further revealed complement-rich adventitial fibroblasts, granzyme K (GZMK)⁺ CD8 T cells, and activated macrophages forming proinflammatory niches within the pulmonary artery adventitia in the different pulmonary vascular lesions in PAH. Our recent work highlights the role of both extracellular and intracellular complement activation in fibroblast-mediated pulmonary vascular inflammation. Specifically, activation of the alternative pathway within fibroblasts, through complement factors D (CFD) and B (CFB), promotes production of anaphylatoxins (C3a and C5a), cytokines, and complement-containing extracellular vesicles (EVs). These mediators drive macrophage and T-cell recruitment and activation, contributing to disease progression. Additionally, a fourth pathway of complement activation mediated by CD8⁺ T cell-derived GZMK, which triggers extracellular complement cascades in fibroblasts and macrophages, has recently been identified. These findings support the hypotheses that local complement production by pulmonary artery adventitial fibroblasts, activated intracellularly by CFD and CFB and extracellularly by GZMK⁺, and its secretion in soluble form and within EVs promotes macrophage chemotaxis and activation. These complement-driven proinflammatory niches in PAH pulmonary arteries represent promising therapeutic targets in PH.