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

## TL;DR

This study shows that targeting CSF1R systemically reduces harmful immune cell clusters and inflammation in psoriasis by activating PPARα.

## Contribution

The study identifies a novel CSF1R-PPARα axis in psoriasis and shows that systemic CSF1R targeting is more effective than local treatment.

## Key findings

- CSF1Rhigh MPS cells form cytokine hubs with elevated TNF-α, IL-1β, and IL-23 in psoriasis.
- Systemic CSF1R targeting disrupts MPS circuits and reduces pro-inflammatory cytokines more effectively than local blockade.
- CSF1R inhibition activates PPARα, which is essential for suppressing inflammation and promoting resolution.

## Abstract

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.