Stroke-induced Immunodeficiency Promotes Spontaneous Bacterial Infections and Is Mediated by Sympathetic Activation Reversal by Poststroke T Helper Cell Type 1–like Immunostimulation

Abstract

Infections are a leading cause of death in stroke patients. In a mouse model of focal cerebral ischemia, we tested the hypothesis that a stroke-induced immunodeficiency increases the susceptibility to bacterial infections. 3 d after ischemia, all animals developed spontaneous septicemia and pneumonia. Stroke induced an extensive apoptotic loss of lymphocytes and a shift from T helper cell (Th)1 to Th2 cytokine production. Adoptive transfer of T and natural killer cells from wild-type mice, but not from interferon (IFN)-γ–deficient mice, or administration of IFN-γ at day 1 after stroke greatly decreased the bacterial burden. Importantly, the defective IFN-γ response and the occurrence of bacterial infections were prevented by blocking the sympathetic nervous system but not the hypothalamo-pituitary-adrenal axis. Furthermore, administration of the β-adrenoreceptor blocker propranolol drastically reduced mortality after stroke. These data suggest that a catecholamine-mediated defect in early lymphocyte activation is the key factor in the impaired antibacterial immune response after stroke.

Inhibition of CXCL12 Signaling Attenuates the Postischemic Immune Response and Improves Functional Recovery after Stroke

“…Our results also support the idea that CXCR4 antagonism may actively block programmed cell death in spleen. 8 The mechanisms by which inhibiting the CXCL12 pathway improves recovery could be due to a direct action on CXCR4/7 expressing detrimental immune cells. Alternatively, CXCR4 antagonism may modulate neurotransmission by direct action on neurons 21 or reactive astrocytes 37 in the peri-infarct area, thereby promoting a milieu permissive for the formation of new neuronal circuits in the ischemic hemipshere.…”

“…7 In addition to local inflammatory processes in the brain, stroke also activates an immune response in peripheral lymphoid organs such as the spleen and thymus. 8 The peripheral immune response is preferentially mediated by the sympathetic nervous systems, leading to apoptosis and atrophy of the spleen and thymus and a subsequent immunodepression. [8][9][10] Since immunomodulators such as cytokines and chemokines are also neuromodulators, brain cells and the immune system may cross-talk and influence brain function and plasticity.…”

Experimental Stroke-Induced Changes in the Bone Marrow Reveal Complex Regulation of Leukocyte Responses

“…As stroke-induced immunodeficiency is a known cause of serious bacterial infections in stroke patients and impairs outcome (Dirnagl et al, 2007;Prass et al, 2003), we investigated whether this response can manifest in the bone marrow. Total bone marrow cells isolated at 72 hours reperfusion expressed and released high levels of interleukin-6 after stimulation with lipopolysaccharide in vitro ( Figures 6A and 6B).…”

“…However, no difference between stroke and sham surgery was observed ( Figures 6A to 6D), indicating that bone marrow cells after stroke retain their ability to respond to stimulation by bacterial cell-wall compounds. The chronic effect of stroke on lymphopaenia in the blood, thymus, and spleen, and impaired cytokine expression by blood cells in response to lipopolysaccharide or mitogens, are apparent 12 to 48 hours after stroke in mice (Prass et al, 2003). (C) C-kit + Gr-1 int mast cell proportions and (D) yield at various reperfusion times.…”

“…Acute or chronic inflammatory diseases often precede and contribute to the onset and outcome of stroke in humans and experimental animals, in part through immune cells such as neutrophils or monocytes and various soluble inflammatory mediators (Denes et al, 2010;Emsley and Hopkins, 2008;McColl et al, 2009). Both clinical and experimental cerebral ischaemia induces activation of the sympathetic nervous system and lymphoid organs such as the spleen, followed by later immunosuppression and splenic atrophy (Dirnagl et al, 2007;Offner et al, 2006bOffner et al, , 2009Prass et al, 2003). These data indicate that the generation of the stroke-induced acute-phase response involves both humoural and neural signals to various peripheral organs.…”