CXCL10 Is Inhibited by PPARβ/δ-Selective Activation in Human Monocyte-Derived Dendritic Cells, T Lymphocytes and Monocytes In Vitro: Insights into Autoimmune Rheumatic Diseases

Abstract

The chemokine CXCL10 contributes to early autoimmune rheumatic disease (ARD) development. Preclinical ARD stages exhibit dendritic cells (DCs), CD4+ T cells, and monocytes (CD14+ cells) dysregulation and an overreactive immunoprofile. The peroxisome proliferator-activated receptor (PPAR)β/δ acts as a “molecular brake”, limiting autoimmune overresponse. This study aims to investigate CXCL10 in human monocyte-derived mDCs, CD4+ T cells, and monocytes exposed to PPARβ/δ agonist carbaprostacylin (cPGI2) or PPARγ agonist rosiglitazone (RGZ), to verify drug-class-related effects. Tumor necrosis factor (TNF)α, interferon (IFN)γ, synergistic inducers of CXCL10, and interleukin (IL)-10 were investigated. mDCs, CD4+ T cells, and CD14+ monocytes isolated from healthy donors’ blood were cultured, specifically activated to mimic an overreactive phenotype, and treated for 24–48 h with/without [10 μM] cPGI2 or [5 μM] RGZ (near therapy doses, respectively). Luminex assays quantified cell supernatant analytes; Real-time q-PCR measured cytokine and PPARβ/δ mRNA expression. cPGI2, not RGZ, significantly decreased CXCL10 in mDCs and CD4+ T cells, reduced TNFα in mDCs, CD4+ T and monocytes, and diminished IFNγ in mDCs. IL-10 did not change. cPGI2-induced CXCL10 downregulation, with TNFα and IFNγ decrease, might be relevant, given its early activity in ARD development. Scenarios on PPARβ/δ agonist re-positioning aimed at modulating CXCL10 might open opportunities to support ARD management and targeted therapy development.