Activation of JAK/STAT3 restores NK‐cell function and improves immune defense after brain ischemia

Abstract

Stroke-induced immune suppression predisposes the host to infections and can contribute to high morbidity and mortality in stroke patients. Because ischemic stroke has a profound effect on the systemic immune response, which may explain the increased susceptibility of stroke patients to infection, an urgent need persists for a better understanding of mechanisms associated with immune suppression; new and effective treatments for stroke can then be identified. NK cells play a key role in early host defense against pathogens by killing infected cells and/or producing cytokines such as IFN-γ. Because the phenotype and function of peripheral NK cells have been widely investigated in ischemic stroke, nCounter Inflammation Gene Array Analysis was used to build immune-related gene profiles of NK cells to comprehensively analyze the molecular signature of NK cells after ischemic brain injury. We observed distinct gene expression profiles reflecting different splenic NK-cell phenotypes and functional properties across the time course of transient middle cerebral artery occlusion (MCAO). Based on gene expression and pathway-network analysis, lower expression levels of signal transducer and activator of transcription-3 (STAT3) were observed in animals with MCAO compared with sham control animals. Genetic activation of STAT3 through the introduction of STAT3 clustered regularly interspaced short palindromic repeats (CRISPR) plasmid prevented the loss of NK-cell-derived IFN-γ production after MCAO, together with reduced bacterial burden and mortality. Our data suggest that brain ischemia impairs NK-cell-mediated immune defense in the periphery, at least in part through the JAK-STAT3 pathway, which can be readdressed by modulating STAT3 activation status.-Jin, W.-N., Ducruet, A. F., Liu, Q., Shi, S. X.-Y., Waters, M., Zou, M., Sheth, K. N., Gonzales, R., Shi, F.-D. Activation of JAK/STAT3 restores NK-cell function and improves immune defense after brain ischemia.

Brain Ischemia Significantly Alters microRNA Expression in Human Peripheral Blood Natural Killer Cells

“…These findings provide clues to further clarify the immunosuppressive mechanism of human NK cells. Consistent with previous studies showing impaired NK cell response after stroke (4,22), these findings suggest that miR-451a and miR-122-5p are possibly involved in the alteration in expression of NK cell surface markers CD69 and NKG2D, but whether miR-451a and miR-122-5p contribute to strokeinduced NK cell deficit needs to be further confirmed by NK cell functional assays.…”

Identification of an Immune-Related Nine-lncRNA Signature Predictive of Overall Survival in Colon Cancer

“…The expression and dysregulation of immune-related genes (IRGs) are involved in the regulation of the immune system. The activation of the JAK/STAT3 signaling pathway restores natural killer cell function and improves immune defense after cerebral ischemia (Jin et al, 2018). A related study found that galectin-1 restores immune tolerance to liver transplant patients by activating hepatic stellate cells (Jiang et al, 2018).…”

Silencing the lncRNA Maclpil in pro-inflammatory macrophages attenuates acute experimental ischemic stroke via LCP1 in mice

“…Various immune cells including T cells, B cells, NK cells, and macrophages have been shown to be involved in stroke-induced neuroinflammation. [3][4][5] Among these cell types, macrophages vastly outnumber all other leukocytes in the ischemic brain. They receive signals from other leukocytes as well as affect other leukocytes by releasing inflammatory factors, thus they are a central player in stroke-induced neuroinflammation.…”