Role of TREM-1 in the development of early brain injury after subarachnoid hemorrhage.

Triggering receptor expressed on myeloid cells-1 (TREM-1) was found to be induced in the context of subarachnoid hemorrhage (SAH) before. This study further investigates its role in the development of SAH-induced early brain injury (EBI). Firstly, rats were randomly divided into Sham and SAH groups for analysis of temporal patterns and cellular localization of TREM-1. Secondly, TREM-1 intervention was administrated to produce Sham, vehicle, antagonist and agonist groups, for analyzing TREM-1, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and NF-κB expressions at 24 h post-modeling, and EBI assessment at 24 h and 72 h. Thirdly, TLR4 inhibitor (TAK-242) was exploited to produce Sham, Sham+TAK-242, SAH, and SAH + TAK-242 groups to analyze the effects of TLR4 inhibition on TREM-1 induction and EBI evaluation at 72 h. Fourthly, the relationship of soluble TREM-1 (sTREM-1) levels in cerebrospinal fluid of SAH patients with Hunt-Hess grades were explored. The results showed that TREM-1 increased in the brain after experimental SAH (eSAH) early at 6 h and peaked at 48 h, which was found to be located in microglia and endothelial cells. TREM-1 inhibition attenuated EBI associated with TLR4/MyD88/NF-κB suppression, while enhancement had the opposite effects. Contrarily, TLR4 inhibition prevented TREM-1 induction and ameliorated EBI. In addition, sTREM-1 levels in SAH patients positively correlated with Hunt-Hess grades. Overall, the present study provides new evidence that TREM-1 increases dynamically in the brain after eSAH and it is located in microglia and endothelial cells, which may aggravate EBI by interacting with TLR4 pathway. And sTREM-1 in patients might act as a monitoring biomarker of EBI, providing new insights for future studies.

Interaction of Microglia and Astrocytes in the Neurovascular Unit.

The interaction between microglia and astrocytes significantly influences neuroinflammation. Microglia/astrocytes, part of the neurovascular unit (NVU), are activated by various brain insults. The local extracellular and intracellular signals determine their characteristics and switch of phenotypes. Microglia and astrocytes are activated into two polarization states: the pro-inflammatory phenotype (M1 and A1) and the anti-inflammatory phenotype (M2 and A2). During neuroinflammation, induced by stroke or lipopolysaccharides, microglia are more sensitive to pathogens, or damage; they are thus initially activated into the M1 phenotype and produce common inflammatory signals such as IL-1 and TNF-α to trigger reactive astrocytes into the A1 phenotype. These inflammatory signals can be amplified not only by the self-feedback loop of microglial activation but also by the unique anatomy structure of astrocytes. As the pathology further progresses, resulting in local environmental changes, M1-like microglia switch to the M2 phenotype, and M2 crosstalk with A2. While astrocytes communicate simultaneously with neurons and blood vessels to maintain the function of neurons and the blood-brain barrier (BBB), their subtle changes may be identified and responded by astrocytes, and possibly transferred to microglia. Although both microglia and astrocytes have different functional characteristics, they can achieve immune "optimization" through their mutual communication and cooperation in the NVU and build a cascaded immune network of amplification.

Early elevated levels of soluble triggering receptor expressed on myeloid cells-1 in subarachnoid hemorrhage patients.

Early brain injury (EBI) contributes to poor prognosis of subarachnoid hemorrhage (SAH). This study aimed to clarify whether triggering receptor expressed on myeloid cells-1 (TREM-1) was implicated in the inflammatory mechanisms of EBI. The cerebrospinal fluid (CSF) levels of soluble TREM-1 (sTREM-1), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) as well as plasma levels of white blood cells (WBC) count and C-reactive protein in 17 SAH patients at early stage (within the EBI period) and 9 volunteers were observed. Also World Federation of Neurosurgical Societies (WFNS) scale of SAH patients was calculated on admission. Compared to controls, increased CSF levels of sTREM-1 (t = 5.66, P < 0.001), TNF-α (t = 5.41, P < 0.001) and IL-6 (t = 2.98, P = 0.007) as well as elevated plasma WBC counts (t = 7.61, P < 0.001) and C-reactive protein levels (t = 3.91, P = 0.001) were found in SAH patients. Considering the increased WBC counts in SAH group, covariate analysis was also performed when comparing patients' sTREM-1 levels with respect to controls and no obvious difference was found (F = 0.982, P = 0.332). For SAH group, early CSF concentrations of sTREM-1 were correlated with those of both TNF-α (r = 0.582, P = 0.014) and IL-6 (r = 0.593, P = 0.012). Also the CSF sTREM-1 levels were positively correlated with WBC counts (r = 0.629, P = 0.007) and C-reactive protein levels (r = 0.804, P < 0.001) as well as WFNS scale (r = 0.835, P < 0.001). This study showed an early increased sTREM-1 CSF level in SAH patients, which correlated with inflammation intensity post-SAH and clinical severity, indicating that TREM-1 may participate in the inflammatory mechanisms of EBI.

Increased levels of soluble triggering receptor expressed on myeloid cells-1 in cerebrospinal fluid of subarachnoid hemorrhage patients.

Triggering receptor expressed on myeloid cells-1 (TREM-1) has been highlighted as a key amplifier of inflammatory response in various diseases. To determine the contribution of TREM-1 in the inflammatory cascade after subarachnoid hemorrhage (SAH), concentrations of soluble TREM-1 (sTREM-1) in cerebrospinal fluid (CSF) from 30 SAH patients and 9 healthy volunteers were measured by enzyme-linked immunosorbent assay. It was shown that the CSF sTREM-1 levels of SAH patients increased significantly than that of the volunteers (P<0.05). Interestingly, the levels were up-regulated dynamically over time with an early increase within 2days and a late peak at day 6 after SAH onset. In addition, it was found that the early sTREM-1 levels (within 3days post-SAH) were negatively correlated with Glasgow Coma Scale (r=-0.550, P=0.022) and positively correlated with the Hunt and Hess scale (r=0.603, P=0.010) respectively conducted on admission, also the early sTREM-1 levels were negatively correlated with Glasgow Outcome Scale (r=-0.505, P=0.039) and positively correlated with modified Rankin Scale (r=0.557, P=0.020) respectively conducted one month after SAH. Altogether, this is the first study showing CSF sTREM-1 dynamics in SAH patients, and exploring the correlations of early CSF sTREM-1 levels to patients' severity and prognosis, which suggests that TREM-1 may play an important role in the inflammatory cascade after SAH and act as a monitoring biomarker facilitated to assess the severity and prognosis of SAH patients.

STAT3 signal that mediates the neural plasticity is involved in willed-movement training in focal ischemic rats.

Willed-movement training has been demonstrated to be a promising approach to increase motor performance and neural plasticity in ischemic rats. However, little is known regarding the molecular signals that are involved in neural plasticity following willed-movement training. To investigate the potential signals related to neural plasticity following willed-movement training, littermate rats were randomly assigned into three groups: middle cerebral artery occlusion, environmental modification, and willed-movement training. The infarct volume was measured 18 d after occlusion of the right middle cerebral artery. Reverse transcription-polymerase chain reaction (PCR) and immunofluorescence staining were used to detect the changes in the signal transducer and activator of transcription 3 (STAT3) mRNA and protein, respectively. A chromatin immunoprecipitation was used to investigate whether STAT3 bound to plasticity-related genes, such as brain-derived neurotrophic factor (BDNF), synaptophysin, and protein interacting with C kinase 1 (PICK1). In this study, we demonstrated that STAT3 mRNA and protein were markedly increased following 15-d willed-movement training in the ischemic hemispheres of the treated rats. STAT3 bound to BDNF, PICK1, and synaptophysin promoters in the neocortical cells of rats. These data suggest that the increased STAT3 levels after willed-movement training might play critical roles in the neural plasticity by directly regulating plasticity-related genes.

Effects of problem-oriented willed-movement therapy on motor abilities for people with poststroke cognitive deficits.

BACKGROUND AND PURPOSE: Cognitive deficits after stroke are common and interfere with recovery. One purpose of this study was to determine whether the motor abilities of subjects who have poststroke cognitive deficits and who have received problem-oriented willed-movement (POWM) therapy will improve more than the motor abilities of subjects in the reference group who have received neurodevelopmental treatment (NDT). Another purpose of this study was to identify the relationship between cognitive function and motor abilities for both groups. SUBJECTS: The subjects recruited for this study were 36 men and 11 women with various degrees of poststroke cognitive deficits. METHODS: A randomized block design was used to assign the subjects to 2 groups. Cognitive function and motor ability were evaluated with the Mini-Mental State Examination and the Stroke Rehabilitation Assessment of Movement (STREAM). Both groups received physical therapy 5 or 6 times per week in 50-minute sessions. RESULTS: The STREAM scores improved after treatment in both groups. Main group effects were found for the lower-extremity (F=4.58, P< .05) and basic mobility (F=27.49, P< .01) subscales of the STREAM. Pretest cognitive function showed a positive relationship with posttest motor ability in the NDT group (r = .446, P< .05). However, the relationship between pretest cognitive function and posttest motor ability had no statistical significance in the POWM group (r = .101, P= .630). DISCUSSION AND CONCLUSION: These findings suggest that, regardless of a person's cognitive function, POWM intervention is effective in improving lower-extremity and basic mobilities and indicates the need to use relatively intact cognitive function or perceptual function, or both, to improve motor rehabilitation for people with cognitive function deficits.