TREM2-stimulated, PDGF-dependent macrophage-fibroblast crosstalk induces beneficial plaque remodeling in clonal hematopoiesis

Background: In Jak2V617F clonal hematopoiesis, inflammatory signaling suppresses macrophage TREM2 and promotes features of plaque instability, while therapeutic TREM2 agonism reverses plaque instability by increasing fibroblasts and fibrous cap formation. We tested whether macrophage-derived PDGFB and stromal cell PDGFR? signaling mediate this response. Methods: Low allele burden (LAB) Jak2V617F atherosclerosis models were combined with inducible Pdgfb deletion in CX3CR1-lineage monocytes/macrophages or Pdgfra deletion in Col1a2-lineage fibroblast-enriched stromal cells. Mice were treated with the TREM2 agonist 4D9. Plaque composition, macrophage-fibroblast interactions, and aortic stromal cell populations were analyzed. Human WT and JAK2V617F iPSC-derived macrophages were used for validation. Results: TREM2 activation with 4D9 increased macrophage PDGFB production and promoted fibrous cap formation in LAB Jak2V617F atherosclerosis. Deletion of Pdgfb in CX3CR1-lineage cells markedly attenuated the 4D9-mediated increase in fibrous cap area and lesional PDGFR?+ cells, establishing macrophage-derived PDGFB as a key signal for the stromal response. Consistently, Col1a2-lineage Pdgfra deletion abolished the 4D9-induced fibrous cap response without significantly altering lesion or necrotic core area. Single cell RNA-seq identified increased Fmod+ and CD26/Dpp4+ fibroblast populations associated with 4D9 treatment. Fmod+ fibroblasts represented an abundant matrix-associated population, whereas CD26+ fibroblasts showed greatest enrichment, prominent extracellular matrix, collagen organization, and matrix-remodeling programs that were enhanced by 4D9 and attenuated by Pdgfra deletion. The stromal response was also associated with reduced macrophage migration-related programs and predicted chemokine communication from CD26+ fibroblasts to macrophages which was verified by macrophage migration studies. Moreover, stromal Pdgfra deletion increased lesional CCR2+ and CCR5+ macrophages. Conclusions: In a CH model of inflammatory atherosclerosis, TREM2 activation promotes a macrophage PDGFB-stromal PDGFR? pathway that expands Fmod+ and CD26+ fibroblast populations and increases fibrous cap matrix formation. CD26+ fibroblasts impair macrophage chemotaxis in a DPP4-dependent manner, suggesting reciprocal macrophage-fibroblast communication that coordinates matrix remodeling and inflammatory cell trafficking in the plaque.