Systemic CSF1R Targeting Depletes Pathogenic MPS Bubs and Ameliorates Psoriasis via PPARα-mediated Resolution.

Rationale: Psoriasis features persistent activation of the mononuclear phagocyte system (MPS), yet the subset-specific pathogenic roles of colony-stimulating factor 1 receptor (CSF1R) remain undefined. We aimed to identify pathogenic CSF1Rhigh MPS subsets, characterize their ligand-receptor circuits, and define the CSF1R-PPARα axis in disease pathogenesis. Methods: By integrating human single-cell and spatial transcriptomics with murine imiquimod (IMQ)-induced psoriasis models, we employed genetic and pharmacologic interventions to achieve our aims. Results: We found a pathologic CSF1Rhigh MPS population was selectively expanded, forming localized cytokine hubs enriched for TNF-α, IL-1β, and IL-23. Ligand mapping showed CSF1 upregulation amplified MPS activation via autocrine loops. Systemic CSF1R targeting dismantled skin-blood MPS circuits and depleted pathogenic hubs, suppressing pro-inflammatory cytokines more effectively than local blockade. Mechanistically, CSF1R activation directly suppressed PPARα. Critically, the anti-inflammatory effect of CSF1R inhibition was abrogated by PPARα antagonism, demonstrating a non-redundant, downstream role for PPARα. Consequently, CSF1R suppression releases PPARα-mediated resolution programs. Pathogenic CSF1Rhigh MPS hubs sustain inflammation through ligand-driven expansion and PPARα suppression. Conclusions: Our work delineates a unidirectional CSF1R-PPARα pathogenic axis and demonstrates that systemic CSF1R targeting is required to disrupt this circuit, providing a mechanistic foundation for a novel treatment strategy.