Editors' ChoiceImmunology

HDL-S1P limits hematopoiesis

Sci. Signal.  28 Jul 2015:
Vol. 8, Issue 387, pp. ec205
DOI: 10.1126/scisignal.aad0392

The phospholipid sphingosine 1-phosphate (S1P) regulates many physiological processes, including the egress of lymphocytes from the thymus and secondary lymphoid organs into the blood and lymph. Much of the S1P in blood is bound to apolipoprotein M (ApoM)–containing high-density lipoprotein (HDL) particles (ApoM+ HDL). Using mice lacking ApoM (Apom–/– mice), Blaho et al. found that ApoM was required for normal S1P concentrations in the blood, but not in lymph. Whereas mice lacking the S1P receptor S1P1 (S1pr1–/– mice) exhibited severe lymphopenia, mice lacking ApoM (Apom–/– mice) had abnormally high numbers of some types of differentiated T and B cells in circulation (a condition called lymphocytosis) and in the lymph, implying that lymphocyte egress did not require ApoM-bound S1P. Lymphopenia was induced in Apom–/– mice by treating these mice with a compound that reduces S1P responsiveness by inducing internalization of S1P1. Examination of the bone marrow of Apom–/– mice revealed increased numbers of common lymphoid progenitor (CLP) cells and of several different hematopoietic stem and progenitor cells collectively referred to as Lin Sac-1+ cKit+ (LSK) cells. S1P bound to ApoM+ HDL limited proliferation of CLPs and LSKs even when S1P1 was pharmacologically activated, because treatment of animals with an S1P1-selective agonist inhibited proliferation of LSKs and CLPs in Apom–/– mice but not in wild-type mice. This result implies that signaling induced by ApoM+ HDL–S1P is different from that induced by S1P that is not associated with ApoM+ HDL. In contrast, mice overexpressing S1pr1 in the bone marrow showed reduced proliferation of LSK and CLP cells. Experiments measuring the amounts of activated signaling components in CLPs from wild-type and Apom–/– mice indicated that ApoM enabled S1P to inhibit proliferation of these cells by activating the extracellular signal–regulated kinase (ERK) pathway. Assays with cultured cells also demonstrated that S1P bound to ApoM+ HDL limited proliferation and differentiation of lymphocyte progenitor cells. Compared with wild-type mice, Apom–/– mice exhibited earlier onset and increased severity of neuroinflammation and blood-brain barrier breakdown following induction of experimental autoimmune encephomyelitis (EAE), a mouse model of multiple sclerosis. Conversely, neuroinflammation after EAE induction was decreased in mice overexpressing human APOM. Thus, ApoM+ HDL–bound S1P limits lymphoid hematopoiesis and restrains the adaptive immune response, but S1P can stimulate lymphocyte egress independently from ApoM+ HDL.

V. A. Blaho, S. Galvani, E. Engelbrecht, C. Liu, S. L. Swendeman, M. Kono, R. L. Proia, L. Steinman, M. H. Han, T. Hla, HDL-bound sphingosine 1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523, 342–346 (2015). [PubMed]