HDL-bound sphingosine 1-phosphate restrains lymphopoiesis and neuroinflammation

Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine 1-phosphate (S1P) is a key regulator of lymphocyte egress(1,2). Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle(3), immunological functions of the ApoM-S1P complex are unknown. Here, we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P(1) receptor on bone marrow (BM) lymphocyte progenitors. Mice that lacked ApoM (Apom(−/−)) had increased proliferation of Lin(−)Sca1(+)cKit(+) hematopoietic progenitor cells (LSK) and common lymphoid progenitors (CLP) in BM. Pharmacologic activation or genetic overexpression of S1P(1) suppressed LSK and CLP proliferation in vivo. ApoM was stably associated with BM CLPs, which showed active S1P(1) signaling in vivo(4). Moreover, ApoM(+)HDL, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(−/−) mice developed more severe experimental autoimmune encephalomyelitis(5), characterized by increased lymphocytes in the central nervous system (CNS) and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P(1) signaling axis restrains the lymphocyte compartment and subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.