Abstract
BackgroundMicroglia/macrophages are known to play important roles in initiating brain inflammation after spontaneous intracerebral hemorrhage (ICH). T cell immunoglobulin and mucin domain-3 (Tim-3) have been proven to play a critical part in several inflammatory diseases through regulation of both adaptive and innate immune responses. Tim-3 can be expressed by microglia/macrophages and regulates their function in the innate immune response. However, the effect of Tim-3 on inflammatory responses following ICH is unclear.MethodsIn this study, we investigated Tim-3 expression, the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and brain water content in peri-hematomal brain tissue at 12 hours and at 1, 3, 5, and 7 days post-ICH in wild type (WT) ICH and Tim-3−/− ICH mice. The numbers of Tim-3 positive cells,astrocytes, neutrophils and microglia/macrophages were detected using immunofluorescence staining. Cytokines were measured by ELISA. Double immunoflurorescence labeling was performed to identify the cellular source of Tim-3 expression. Mouse neurological deficit scores were assessed through animal behavior.ResultsExpression of Tim-3 increased early in mouse peri-hematomal brain tissue after autologous blood injection, peaked at day 1, and was positively correlated with the concentrations of TNF-α, IL-1β, and brain water content. Tim-3 was predominantly expressed in microglia/macrophages. Compared with WT mice, Tim-3−/− mice had reduced ICH-induced brain inflammation with decreased TNF-α and IL-1β, cerebral edema and neurological deficit scores. Moreover, Tim-/- inhibited activation of microglia/macrophages. The number of activated microglia/macrophages in Tim-3−/− ICH mice was much lower than that in WT ICH mice.ConclusionsOur findings demonstrate that Tim-3 plays an important role in brain inflammation after ICH, and may be a potential treatment target.
Highlights
Microglia/macrophages are known to play important roles in initiating brain inflammation after spontaneous intracerebral hemorrhage (ICH)
Considering that the microglia/macrophages are the key cells for inducing brain inflammation and secondary brain damage, and that T cell immunoglobulin and mucin domain-3 (Tim-3) can regulate the function of microglia/macrophages, we hypothesized that Tim-3 possibly took part in ICH-induced inflammation by regulating the function of microglia/macrophages
Increase of Tim-3 expression in the peri-hematomal brain tissues In order to investigate the expression of Tim-3 in the peri-hematomal brain tissues, we observed the number of Tim-3 positive cells in the peri-hematomal brain tissues at 12 hours and at 1, 3, 5 and 7 days post-ICH
Summary
Microglia/macrophages are known to play important roles in initiating brain inflammation after spontaneous intracerebral hemorrhage (ICH). Increasing researches show that inflammatory response plays an important role in ICH-induced secondary brain damage [4,5]. Brain inflammation after ICH is characterized by accumulation of activated inflammatory cells, such as blood-derived cells (macrophages, leukocytes) and brain resident cells (astrocytes, microglia and mast cells). These reactive cells can release inflammatory mediators, including chemokines, cytokine, protease, prostaglandins and other immunoactive molecules [6,7]. Considering that the microglia/macrophages are the key cells for inducing brain inflammation and secondary brain damage, and that Tim-3 can regulate the function of microglia/macrophages, we hypothesized that Tim-3 possibly took part in ICH-induced inflammation by regulating the function of microglia/macrophages This experiment was done to prove our hypothesis
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