Introduction:Intracerebral hemorrhage (ICH) causes devastating morbidity and mortality, and studies have shown that the toxic components of hematomas play key roles in brain damage after ICH. Recent studies have found that TLR9 participates in regulating the phagocytosis of peripheral macrophages. The current study examined the role of TLR9 in macrophage/microglial (M/M) function after ICH. Methods: RAW264.7 (macrophage), BV2 (microglia), and HT22# (neurons) cell lines were transfected with lentivirus for TLR9 overexpression. Whole blood from C57BL/6 or EGFP Tg/+ mice was infused for phagocytosis and injury experiments, and brusatol was used for the experiments. Intraperitoneal injection of the TLR9 agonist ODN1826 or control ODN2138 was performed on days 1, 3, 5, 7, and 28 after ICH to study the effects of TLR9 in mice. In addition, clodronate was coinjected in M/M elimination experiments. The brains were collected for histological and protein experiments at different time points after ICH induction. Cellular and histological methods were used to measure hematoma/iron residual, M/Ms variation, neural injury, and brain tissue loss.Behavioral tests were performed premodeling and on days 1, 3, 7, and 28 post-ICH. Results: Overexpression of TLR9 facilitated M/M phagocytosis and protected neurons from blood-derived hazards in vitro. Furthermore, ODN1826 boosted M/M activation and phagocytic function, facilitated hematoma/iron resolution, reduced brain injury, and improved neurological function recovery in ICH mice, which were abolished by clodronate injection. The experimental results indicated that the Nrf2/ CD204 pathway participated in TLR9-induced M/M phagocytosis after ICH. Conclusion: Our study suggests a protective role for TLR9-enhanced M/M phagocytosis via the Nrf2/CD204 pathway after ICH. Our findings may serve as potential targets for ICH treatment. | 1801 WEI Et al. | INTRODUC TI ONIntracerebral hemorrhage (ICH) is the most severe subtype of stroke and has devastating consequences on families and society. However, there is no desirable treatment for ICH with an absolute benefit. 1 Studies have shown that the toxic components of hematomas trigger immune cell activation as well as a variety of cytokines, chemokines, and free radical release, causing secondary brain injury, and reducing hematoma and/or its toxic components alleviates inflammation as well as injury after ICH. 2-5 Thus, many studies have focused on the pharmacological treatment of ICH, 6 such as the enhancement of erythropagocytosis, mitigation of inflammation, and protection of white matter, but only a small portion of these studies showed promising results. [7][8][9] Peripheral macrophages and resident microglia (macrophage/ microglia, M/M) are important members of the innate immune system that play crucial roles in ICH. Studies have shown that M/Ms are activated at a very early stage post-ICH and participate in hematoma clearance and neuroinflammation modulation. 10 One of the major functions of M/Ms is to phagocytose cell debris and other ...
Intracerebral hemorrhage (ICH) is a devasting stroke type with high mortality and disability. Inflammatory response induced by macrophages/microglia (M/Ms) activation is one of the leading causes of brain damage after ICH. The anti-inflammatory effects of resveratrol (RSV) have already been evaluated in several models of central nervous system disease. Therefore, we designed the current study to assess the role of RSV in ICH and explore its downstream mechanism related to Sirt3. The autologous artery blood injection was administrated to create an ICH mouse model. M/Ms specific Sirt3 knockout Sirt3f/f; CX3CR1-Cre (Sirt3 cKO) mouse was used to evaluate the role of Sirt3 on RSV treatment. Neuronal function and hematoma volume were assessed to indicate brain damage. The pro-inflammatory marker (CD16) and cytokine (TNF-α) were measured to evaluate the inflammatory effects. Our results showed that RSV treatment alleviates neurological deficits, reduces apoptosis, and increases hematoma clearance on day 7 after ICH. In addition, RSV effectively suppressed CD16+ M/Ms activation and decreased TNF-α release. In Sirt3 cKO mice, the protective effects of RSV were abolished, indicating the potential mechanism of RSV was partially due to Sirt3 signaling activation. Therefore, RSV could be a promising candidate and therapeutic agent for ICH and Sirt3 could be a potential target to inhibit inflammation.
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