Table 2.

Milestone discoveries in the study of stroke-induced neuroinflammation

Authors and Journal	Publication Date	Findings	Significance
Giulian et al., Journal of Experimental Medicine	1986	CNS ameboid microglia produce IL-β	First record of cerebral microglia producing cytotoxic/inflammatory compounds, suggesting they play a role in neurodegenerative pathology
Garcia et al, The American Journal of Pathology	1993	Identification of histopathological changes in brain after ischemic stroke, including time-dependent increases in necrosis and cellular damage	Suggested that neurodegeneration can affect the brain constitutively after ischemic stroke, expanded pathological perspective on the disease beyond the primary lesion
Clark et al, Brain Research Bulletin	1993	Identification of immunohistochemical changes in brain following ischemic stroke, including infiltration of neutrophils, necrosis, and activation of astroglia	Early evidence that neutrophils invade cerebral environment following stroke, suggesting peripheral immune response and activated astroglia may exacerbate insult, extra-focal tissue damage
Morioka et al, Journal of Comparative Neurology	1993	Reactive microglia found to be activated within area of ischemic injury and extra-focal areas, microglia activation persisted unilaterally after long-term survival	Reactive microglia implicated as a mediator of both extra-focal neurodegeneration and long-term neuroinflammation following ischemic stroke
Schroeter et al, Journal of Neuroimmunology	1994	Multiple classes of immune cells detected in tissues of the ischemic brain, including neutrophils, T cells, B cells, and macrophages	Significant evidence that peripheral immune cells can infiltrate cerebral environment following ischemic stroke, crossing the blood brain barrier, and possibly exacerbating insult. Overturned notion of brain as an immune-privileged organ.
Kim et al, J of Neuroimmunology	1995	Expression of monocyte chemoattractant protein-1 and macrophage inflammatory protein (MIP-1alpha) elevated in stroke brain and peaks between 24 and 48 hours after ischemic stroke	Provided evidence of macrophage-induced inflammation in the brain, suggested a possible signaling mechanism was being produced to attract pro-inflammatory macrophages
Jander et al, Journal of Cerebral Blood Flow & Metabolism	1995	MIP-alpha expression correlates with detected infiltration of peripheral macrophages after ischemic stroke	Direct evidence that macrophages from peripheral blood are responsible for producing neuroinflammation in the cerebral environment following ischemic stroke
Szaflarski et al, Stroke	1995	Cerebral ischemia stimulates local expression of inflammatory cytokines, TNF-alpha and IL-β	Suggests that neuroinflammation following ischemic stroke may be a product of both an external immune response and cytokine gene expression from endogenous brain cells
Gendron et al, Brain Research	2002	Systemic activation of T and B cell populations following ischemic stroke, absence of asymmetric suppressive effects between cerebral hemispheres, total number of spleen cells decreases after stroke	Evidence ischemic lesion produces a neuroinflammatory effect in both cortical and subcortical areas of either hemisphere, evidence that lesions produce elevated systemic inflammatory mobilization of T and B cells, early acknowledgement of spleen’s potential role in promoting neuroinflammation
Hill et al, Journal of Neuropathology & Experimental Neurology	2004	Chemokine stromal-derived factor-1 (SDF-1) expression elevated in penumbra following ischemic stroke, associated with reactive perivascular astrocytes/microglia	SDF-1 implicated as a signaling molecule in the mobilization of bone-marrow derived cells, notably inflammatory monocytes, to the brain after ischemic stroke
Newman et al, Stem Cells and Development	2005	Cytokine-induced neutrophil chemoattractant-1 (CNC-1) and IL-8 elevated in brain tissue following ischemic stroke, highest during acute phase	Discovery of first chemokine, IL-8, in ischemic brain tissue, suggests this pro-inflammatory factor may play a role in the mobilization and homing of neutrophils to the site of injury
Offner et al, The Journal of Immunology	2006	Ischemic stroke leads to splenic atrophy, reduction in number of splenocytes, resultant reduction in peripheral B cells, upregulation of CD4+FoxP3+regulatory T cells and CD11b+VLA-4-negative macrophages/monocytes	Evidence that spleen plays a role in the regulation of the immune response to ischemic stroke, influencing macrophage/regulator T cell mobilization
Ajmo et al, Journal of Neuroscience Research	2008	Splenectomy results in a significant reduction in lesion volume, numbers of activated microglia, macrophages, and neutrophils in brain tissue following ischemic stroke	Direct evidence that spleen is a major contributor to the development of secondary inflammation and resultant neurodegeneration after ischemic stroke
Seifert et al, Journal of Neuroimmune Pharmacology	2012	Carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled splenocytes (lymphocyte, monocytes, and neutrophils) explicitly visualized migrating to the brain after ischemic injury	Provided resolution as to the mobilization/migration behavior of splenic immune cells following ischemic stroke, demonstrated that after 96h splenocytes develop into pro-inflammatory NK cells, T cells and monocytes
Acosta et al, Stroke	2015	Intravenously injected labeled hBMSCs preferentially migrate to spleen following ischemic stroke, encourage reduction in striatal and peri-striatal infarct, activated inflammatory cells in brain tissue, and TNF-alpha expression in splenic cells, while exercising a neuroprotective effect on hippocampal neuronal cells	Suggests that hBMSCs, and generalized stem cell transplants, may provide a means to abrogate stroke induced neuroinflammation by moderating the intensity of the splenic peripheral immune response and resultant pro-inflammatory activation in brain tissue