Osteopontin promotes inflammation in patients with acute coronary syndrome through its activity on IL-17 producing cells

Atherosclerosis is a progressive disease with a strong inflammatory component. Here we confirm the existence of a critical imbalance in the ratio of Th17 to Treg-cell populations in peripheral CD4⁺ T cells from patients with acute coronary syndrome (ACS), which favors inflammation. This was concurrent with increased IL-17 production from the CD4⁺CD45RA^-FOXP3^lo Treg-cell subset, and elevated osteopontin (OPN) levels in serum from ACS patients. We demonstrate a direct effect of OPN in serum from ACS patients on increased IL-17 production by CD4⁺CD45RA^-FOXP3^lo T cells, mediated through recruitment of the OPN receptors CD29 and CD44, and dependent on STAT3 and the nuclear hormone receptor retinoic-acid-related orphan receptor-γt (RORγt) pathway, but not IL-6 production. To our knowledge and beyond the disease context of ACS, this study constitutes the first demonstration of a critical role for OPN in the positive regulation of inflammation through increased IL-17 production by CD4⁺CD45RA^-FOXP3^lo cells.