Multiplex immunoassay characterization and species comparison of inflammation in acute and non-acute ischemic infarcts in human and mouse brain tissue.
This study provides a parallel characterization of the cytokine and chemokine response to stroke in the human and mouse brain at different stages of infarct resolution. The study goal was to address the hypothesis that chronic inflammation may contribute to stroke-related dementia. We used C57BL/6 and BALB/c mice to control for strain related differences in the mouse immune response. Our data indicate that in both mouse strains, and humans, there is increased granulocyte macrophage colony-stimulating factor (GM-CSF), interleukin-6 (IL-6), interleukin-12 p70 (IL-12p70), interferon gamma-induced protein-10 (IP-10), keratinocyte chemoattractant/interleukin-8 (KC/IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β), regulated on activation, normal T cell expressed and secreted (RANTES), and Tumor necrosis factor-α (TNF-α) in the infarct core during the acute time period. Nevertheless, correlation and two-way ANOVA analyses reveal that despite this substantial overlap between species, there are still significant differences, particularly in the regulation of granulocyte colony-stimulating factor (G-CSF), which is increased in mice but not in humans. In the weeks after stroke, during the stage of liquefactive necrosis, there is significant resolution of the inflammatory response to stroke within the infarct. However, CD68+ macrophages remain present, and levels of IL-6 and MCP-1 remain chronically elevated in infarcts from both mice and humans. Furthermore, there is a chronic T cell response within the infarct in both species. This response is differentially polarized towards a T helper 1 (Th1) response in C57BL/6 mice, and a T helper 2 (Th2) response in BALB/c mice, suggesting that the chronic inflammatory response to stroke may follow a different trajectory in different patients. To control for the fact that the average age of the patients used in this study was 80 years, they were of both sexes, and many had suffered from multiple strokes, we also present findings that reveal how the chronic inflammatory response to stroke is impacted by age, sex, and multiple strokes in mice. Our data indicate that the chronic cytokine and chemokine response to stroke is not substantially altered in 18-month old compared to 3-month old C57BL/6 mice, although T cell infiltration is attenuated. We found a significant correlation in the chronic cytokine response to stroke in males and females. However, the chronic cytokine response to stroke was mildly exacerbated by a recurrent stroke in both C57BL/6 and BALB/c mice.
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.|Department of Neurology, University of Arizona College of Medicine, Tucson, AZ, USA.
Thuy-Vi V
TV
Nguyen
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
Jennifer B
JB
Frye
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
Jacob C
JC
Zbesko
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
Kristina
K
Stepanovic
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
Megan
M
Hayes
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA.
Alex
A
Urzua
Banner Sun Health Research Institute, Sun City, AZ, USA.
Geidy
G
Serrano
Banner Sun Health Research Institute, Sun City, AZ, USA.
Thomas G
TG
Beach
Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA. doylekr@email.arizona.edu.|Department of Neurology, University of Arizona College of Medicine, Tucson, AZ, USA. doylekr@email.arizona.edu.|Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ, USA. doylekr@email.arizona.edu.
Kristian P
KP
Doyle
D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology; D020520:Brain Infarction / Q000276:immunology* / Q000473:pathology; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007118:Immunoassay; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012008:Recurrence; D012727:Sex Characteristics; D013045:Species Specificity
Chronic infarcts; Cytokines; Inflammation; Liquefactive necrosis; Stroke