Elsevier

Neuroscience

Volume 158, Issue 3, 6 February 2009, Pages 1098-1111
Neuroscience

Review
Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression

https://doi.org/10.1016/j.neuroscience.2008.05.033Get rights and content

Abstract

The profound damage to the CNS caused by ischemic lesions has been well documented. Yet, relatively little is known about the contribution to and effects on the immune system during stroke. We have focused on both early and late events in the peripheral immune system during stroke in mice and have observed an early activation of splenocytes that conceivably could result in immune-mediated damage in the developing CNS lesion, followed by global immunosuppression that affects the spleen, thymus, lymph nodes and circulation. While this second immunosuppressive phase may not directly enhance infarction size, it without doubt leads to an inability to respond to antigenic challenges, thereby enhancing the risk for crippling systemic infection and septicemia in stroke survivors. These novel findings advocate the need to develop or effectively utilize agents that can block early neural splenic activation and modulate immune cells specific for brain antigens as a means to prevent mobilization of T and B cells carrying a cytokine death warrant to the brain. Equally important for the recovering stroke patient are approaches that can derail the second phase of immune dysfunction and restore the ability to mount a defense against systemic infectious insults.

Section snippets

Stroke-induced changes in immune responses

Clinical stroke and experimental cerebral ischemia induce local inflammatory processes that undoubtedly contribute to total cerebral injury (Allan and Rothwell 2003, del Zoppo et al 2001). Within hours, transcription factors are activated locally in brain tissue (e.g. nuclear factor-κB (O'Neill and Kaltschmidt, 1997)) that up-regulate pro-inflammatory genes, including the cytokines tumor necrosis factor α (TNF-α) (Liu et al., 1994), interleukin 1β (IL-1β) (Liu et al 1993, Wang et al 1994), IL-6

Stroke-induced immunosuppression

Early activation of systemic immunity is likely transient. Immunodeficiency following stroke has been widely observed and appears to contribute significantly to widespread infections that are often lethal. A previous report demonstrated a reduction in the number of immune cells and a significant increase in the percent of terminal UDP-nick end labeling (TUNEL)+ B cells, T cells, and natural killer (NK) cells in blood, spleen and thymus in mice after stroke (Prass et al., 2002). The reduced cell

Importance of T and B cells to the stroke lesion

T cells have been identified by immunohistochemistry in post-ischemic brain as early as 24 h after reperfusion, and appear localized to infarction boundary zones, typically close to blood vessels (Schroeter et al 1994, Jander et al 1995). Antibodies against rat α4 integrin that prevents lymphocyte infiltration into post-ischemic brain can reduce damage after transient MCAO (Becker et al 2001, Relton et al 2001). However, the importance of T lymphocytes in the quantity and diversity of

Conclusions and a working model of post-stroke immunopathology

Animal data clearly support a biphasic effect of stroke on the peripheral immune system. The initial phase is characterized by early signaling from the ischemic brain to spleen, resulting in a massive production of inflammatory factors and transmigration of splenocytes to the circulation and brain. This early activation phase is followed by systemic immunosuppression that is manifested within days of focal stroke by a reduction in T cell activation and a profound loss of immune T and B cells in

Acknowledgments

The authors wish to thank Ms. Eva Niehaus for assistance in preparing and submitting the manuscript and Dr. Wenri Zhang and Ms. Susan Parker for the preparation of cerebral blood flow autoradiography in the SCID mice. This work was supported by US Public Health Service NIH grants NS33668, NR03521, NS49210, RR00163, and the Biomedical Laboratory R&D Service, Department of Veterans Affairs.

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