Abstract
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 (PGD
2
) is traditionally viewed as an extracellular mediator in allergic diseases. Here, we identify PGD
2
as a cell-intrinsic antagonist of the nuclear receptor PPAR
γ
, thereby promoting Th17 cell differentiation and exacerbating EAE pathology. PGD
2
is selectively elevated in patients with MS compared with healthy individuals. Within the MS cohort, PGD
2
correlates with Th17 cell frequency and disease severity. Consistent with this association, administration of PGD
2
increases the severity of experimental autoimmune encephalomyelitis (EAE) in mice. CD4
+
T cell-specific deletion of
Hpgds
, the key synthase for PGD
2
, impairs Th17 cell polarization and protects against EAE, whereas exogenous PGD
2
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, PGD
2
binds directly to histidine 266 and serine 342 within the PPAR
γ
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-PGD
2
axis in Th17 cell-mediated autoimmunity, establishing HPGDS as a promising therapeutic target for Th17 cell-mediated autoimmune diseases such as MS.