Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4(+) T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of 2D2 and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of 2D2 mice 14 d after middle cerebral artery occlusion. One month after experimental stroke, 2D2 mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4(+) T cells, isolated from 2D2 mice, into lymphocyte-deficient Rag-1KO mice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.
Current multiple sclerosis (MS) therapies only partially prevent chronically worsening neurological deficits, which are largely attributable to progressive loss of CNS axons. Prior studies of experimental autoimmune encephalomyelitis (EAE) induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide), a model of MS, documented continued axon loss for months after acute CNS inflammatory infiltrates had subsided, and massive astroglial induction of CCL2 (MCP-1), a chemokine for CCR2(+) monocytes. We now report that conditional deletion of astroglial CCL2 significantly decreases CNS accumulation of classically activated (M1) monocyte-derived macrophages and microglial expression of M1 markers during the initial CNS inflammatory phase of MOG peptide EAE, reduces the acute and long-term severity of clinical deficits and slows the progression of spinal cord axon loss. In addition, lack of astroglial-derived CCL2 results in increased accumulation of Th17 cells within the CNS in these mice, but also in greater confinement of CD4(+) lymphocytes to CNS perivascular spaces. These findings suggest that therapies designed to inhibit astroglial CCL2-driven trafficking of monocyte-derived macrophages to the CNS during acute MS exacerbations have the potential to significantly reduce CNS axon loss and slow progression of neurological deficits.