What question did this study set out to answer?

This research aims to understand how intracellular complement factor D (CFD) influences inflammation and immune responses in pulmonary hypertension (PH).

May 20, 2026

A107-03 Intracellular Complement Factor D Enhances Activation of Adventitial Fibroblasts to Promote Inflammation and Immune Crosstalk in Pulmonary Hypertension

Key Points

This research aims to understand how intracellular complement factor D (CFD) influences inflammation and immune responses in pulmonary hypertension (PH).
Utilized precision-cut lung slices (PCLS) from healthy and PH-affected bovines and humans.
Investigated the effects of pharmacological CFD inhibition using ALXN2050 on inflammatory signal production.
Analyzed gene expression changes in response to hypoxia and IL-1β stimulation in co-culture models with macrophages.
ALXN2050 significantly reduced C3a production and proinflammatory markers like CCL2, CXCL12, and IL6 in pulmonary hypertension samples.
Combined IL-1β and hypoxia in healthy PCLS led to increased inflammation, which was tempered by CFD inhibition.
In co-culture models, hypoxia-induced macrophage infiltration was markedly lessened with ALXN2050 treatment.

Abstract

Abstract Background Pulmonary hypertension (PH) is a progressive and ultimately fatal vascular disease characterized by perivascular inflammation and remodeling driven by persistently activated adventitial fibroblasts that adopt a proinflammatory and metabolically reprogrammed phenotype. Emerging evidence implicates the complement system, including local intracellular complement activity (the “complosome”), as a critical regulator of these processes. Our recent studies demonstrated that intracellular complement proteins C3, CFB, and particularly CFD are essential for maintaining fibroblast activation in PH. Within fibroblasts, CFD interacts with CFB to activate C3, generating C3a that signals through mitochondrial C3aR1 to modulate metabolic and inflammatory programs. However, these mechanisms have primarily been studied in isolated cell cultures, which fail to recapitulate the complex tissue microenvironment. To address this limitation, we employed precision-cut lung slices (PCLS) to investigate CFD-mediated inflammatory signaling and immune-stromal crosstalk in situ. Methods and Results Using human and bovine PCLS, we examined the impact of pharmacological CFD inhibition via ALXN2050, which inhibits intracellular CFD, on complement activation and inflammatory signaling. In PCLS derived from bovines with established PH, ALXN2050 markedly reduced C3a production and suppressed expression of key proinflammatory mediators, including CCL2, CXCL12, and IL6. In healthy human and bovine PCLS, combined IL-1β stimulation and hypoxia induced a robust inflammatory transcriptional response (IL6, CCL2, CXCL12, C3), which was significantly attenuated by CFD inhibition. Furthermore, in a hypoxia-induced co-culture model of PCLS with bone marrow-derived macrophages (BMDMs), hypoxia promoted macrophage infiltration and upregulation of IL1B, CCL5, CXCL12, and C3 responses that were substantially blunted by ALXN2050 treatment. Conclusion These findings establish intracellular CFD in adventitial fibroblasts as a key mediator of inflammation and immune cell recruitment in PH. Pharmacological inhibition of CFD effectively suppresses complement activation, inflammatory gene expression, and macrophage infiltration in native lung tissue, identifying CFD as a promising therapeutic target to disrupt the self-sustaining inflammatory milieu that drives pulmonary vascular remodeling in PH. This abstract is funded by: NHLBI P01HL014985; DOD/W81XWH1910259; DoD/W81XWH2010249

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