Recent evidence has shown that an increase in CD4(+)CD25(+)FoxP3(+) regulatory T (Treg) cells may contribute to
stroke-induced immunosuppression. However, the molecular mechanisms that underlie this increase in Treg cells remain unclear. Here, we used a transient
middle cerebral artery occlusion model in mice and specific pathway inhibitors to demonstrate that
stroke activates the sympathetic nervous system, which was abolished by
6-OHDA. The consequent activation of β2-adrenergic receptor (AR) signaling increased
prostaglandin E2 (
PGE2) level in bone marrow. β2-AR antagonist prevented the upregulation of
PGE2.
PGE2, which acts on
prostaglandin E receptor subtype 4 (EP4), upregulated the expression of receptor activator for NF-κB
ligand (RANKL) in CD4(+) T cells and mediated the increase in Treg cells in bone marrow. Treatment of MCAO mice with RANKL antagonist OPG inhibited the increase in percent of bone marrow Treg cells.
PGE2 also elevated the expression of
indoleamine 2,3 dioxygenase in CD11C(+) dendritic cells and promoted the development of functional Treg cells. The effect was neutralized by treatment with
indomethacin. Concurrently,
stroke reduced production of stromal cell-derived factor-1 (SDF-1) via β3-AR signals in bone marrow but increased the expression of
C-X-C chemokine receptor (CXCR) 4 in Treg and other bone marrow cells. Treatment of MCAO mice with β3-AR antagonist
SR-59230A reduced the percent of Treg cells in peripheral blood after
stroke. The disruption of the CXCR4-SDF-1 axis may facilitate mobilization of Treg cells and other CXCR4(+) cells into peripheral blood. This mechanism could account for the increase in Treg cells, hematopoietic stem cells, and progenitor cells in peripheral blood after
stroke. We conclude that
cerebral ischemia can increase bone marrow CD4(+)CD25(+)FoxP3(+) regulatory T cells via signals from the sympathetic nervous system.