CD11b+/Gr-1int monocytic myeloid derived suppressor cells contribute to high-fat induced inflammation and delayed tolerance in mouse liver (54.15)

Abstract

Myeloid derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells with universal expansion in nearly all inflammatory conditions. This study investigated the accumulation of MDSC in chronic inflammation and tolerance of obesity-related fatty liver disease. We found that the expansion of MDSC, specifically associated with the monocytic MDSC (M-MDSC): CD11b+Gr-1intLy6G-Ly6Chigh in the liver of B6 mice fed a high-fat diet contributes to liver inflammation and tolerance. M-MDSCs isolated from the liver of obese mice are more easily activated by way of Toll-like receptor (TLR4) stimulation resulting in inflammatory cytokine expression, and were functional MDSCs, readily inhibiting T cell proliferation in vitro dependent on cell-cell contact between MDSCs and T cells. The rapid accumulation of M-MDSC also contributed to delayed ConA tolerance in obesity-related fatty liver disease. M-MDSCs isolated from the liver of obese mice developed with ConA tolerance induce less liver regulatory T (Treg) cell expansion and less suppressing T cell proliferation in vitro. Experiments using mice depleted of Gr-1, or M- MDSC adoptive transfer demonstrated the important role of M-MDSC in liver inflammation and tolerance. These data unveil that M-MDSCs play an essential negative feedback function in liver immune homeostasis.