Targeting the HPGDS-PGD2 axis to treat Th17 cell-mediated autoimmunity in multiple sclerosis

Abstract

Th17 cells are central drivers of autoimmune pathology, including multiple sclerosis (MS), yet the endogenous metabolic signals that shape their pathogenic differentiation remain incompletely defined. Prostaglandin D₂ (PGD2) is traditionally viewed as an extracellular mediator in allergic diseases. Here, we identify PGD2 as a cell-intrinsic antagonist of the nuclear receptor PPARγ, thereby promoting Th17 cell differentiation and exacerbating EAE pathology. PGD2 is selectively elevated in patients with MS compared with healthy individuals. Within the MS cohort, PGD2 correlates with Th17 cell frequency and disease severity. Consistent with this association, administration of PGD2 increases the severity of experimental autoimmune encephalomyelitis (EAE) in mice. CD4+ T cell-specific deletion of Hpgds, the key synthase for PGD2, impairs Th17 cell polarization and protects against EAE, whereas exogenous PGD2 restores both Th17 cell responses and disease susceptibility. Importantly, pharmacological inhibition of HPGDS alleviates EAE symptoms in mice. Consistently, HPGDS inhibition suppresses Th17 cell differentiation in both murine and human CD4+ T cells, highlighting its translational potential. Mechanistically, PGD2 binds directly to histidine 266 and serine 342 within the PPARγ ligand-binding domain and suppresses its transcriptional activity, as demonstrated by site-directed mutagenesis and structure-function rescue assays in Pparg-/- T cells. Collectively, our findings define a crucial role for the HPGDS-PGD2 axis in Th17 cell-mediated autoimmunity, establishing HPGDS as a promising therapeutic target for Th17 cell-mediated autoimmune diseases such as MS.