Ram Raj Prasad 1, Sushil Kumar 1, Hui Zhang 1, Min Li 1, Cheng-Jun Hu 2, Suzette Riddle 1, Brittany A McKeon 3, M G Frid 1, Konrad Hoetzenecker 4, Slaven Crnkovic 5, Grazyna Kwapiszewska 5, Rubin M Tuder 1, Kurt R Stenmark 1
University of Colorado Anschutz Medical Campus. Medical University of Vienna. Medical University of Graz.
United States and Austria
Journal of Clinical Investigation Insight
JCI Insight 2025;
DOI: 10.1172/jci.insight.184141
Abstract
The complement system is central to the innate immune response, playing a critical role in pro-inflammatory and autoimmune diseases such as pulmonary hypertension (PH). Recent discoveries highlight the emerging role of intracellular complement, or the “complosome,” in regulating cellular processes like glycolysis, mitochondrial dynamics, and inflammatory gene expression. This study investigates the hypothesis that intracellular complement proteins C3, CFB, and CFD are upregulated in PH fibroblasts (PH-Fibs) and drive their metabolic and inflammatory states, contributing to PH progression. Our results reveal a pronounced upregulation of CFD, CFB, and C3 in PH-Fibs from human and bovine models, both in vivo and in vitro. Elevated levels of C3 activation fragments, including C3b, C3d, and C3a, emphasize enhanced C3 activity. PH-Fibs exhibit notable metabolic reprogramming and increased pro-inflammatory mediators such as MCP1, SDF1, IL6, IL13, and IL33. Silencing CFD via shRNA reduced CFB activation and C3a production while normalizing glycolysis, tricarboxylic acid (TCA) cycle activity, and fatty acid metabolism. Metabolomic and gene expression analyses of CFD knockdown PH-Fibs revealed restored metabolic and inflammatory profiles, underscoring CFD’s crucial role in these changes. This study emphasizes the crucial role of intracellular complement in PH pathogenesis, highlighting the potential for complement-targeted therapies in PH.
Category
Class I. Pulmonary Hypertension Associated with Inflammation
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access Free PDF File or Full Text Article Available Through PubMed or DOI: Yes