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Recombinant CCL17 Enhances Hematoma Resolution and Activation of CCR4/ERK/Nrf2/CD163 Signaling Pathway After Intracerebral Hemorrhage in Mice.

ABSTRACT: Hematoma is a crucial factor leading to poor prognosis after intracerebral hemorrhage (ICH). Promoting microglial phagocytosis to enhance hematoma resolution may be an important therapeutic target for recovery after ICH. C-C chemokine receptor 4 (CCR4) is important for regulating immune balance in the central nervous system. However, whether CCR4 activation can attenuate hematoma after ICH remains unknown. We aimed to evaluate whether CCL17 (a specific ligand of CCR4) treatment can promote hematoma resolution through CCR4/ERK/Nrf2/CD163 pathway after ICH. A total of 261 adult male CD1 mice were used. Mice were subjected to intrastriatal injection of autologous blood to induce ICH and randomly assigned to receive recombinant CCL17 (rCCL17) or vehicle which was administered intranasally at 1 h after ICH. To elucidate the underlying mechanism, C021, a selective inhibitor of CCR4 and ML385 and a selective inhibitor of Nrf2 were administered 1 h prior to ICH induction. Clustered regularly interspaced short palindromic repeats (CRISPR) knockout for CD163 was administered by intracerebroventricular injection at 48 h before ICH. Brain edema, short- and long-term neurobehavior evaluation, hematoma volume, hemoglobin content, western blot, and immunofluorescence staining were performed. Endogenous CCL17, CCR4, and CD163 expression increased and peaked at 72 h after ICH. CCR4 was expressed by microglia. CCR4 activation with rCCL17 significantly improved neurobehavioral scores and reduced hematoma volume and brain edema compared with vehicle. Moreover, rCCL17 treatment significantly promoted phosphorylation of ERK1/2, increased the expression Nrf2, and upregulated CD163 expression after ICH. The protective effects of rCCL17 were abolished by administration of C021, ML385, and CD163 CRISPR knockout. This study demonstrated that CCR4 activation with rCCL17 promoted hematoma resolution by increasing CD163 expression and CCR4/ERK/Nrf2 pathway activation after ICH, thereby reducing brain edema and improving neurological function. Overall, our study suggests that CCR4 activation may be a potential therapeutic strategy to attenuate hematoma in early brain injury after ICH.

SUBMITTER: Deng S

PROVIDER: S-EPMC7851239 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveHematoma enlargement (HE) is associated with clinical outcomes after supratentorial intracerebral hemorrhage (ICH). This study evaluates whether HE characteristics and association with functional outcome differ in deep versus lobar ICH.MethodsPooled analysis of individual patient data between January 2006 and December 2015 from a German-wide cohort study (RETRACE, I + II) investigating ICH related to oral anticoagulants (OAC) at 22 participating centers, and from one single-center registry (UKER-ICH) investigating non-OAC-ICH patients. Altogether, 1954 supratentorial ICH patients were eligible for outcome analyses, which were separately conducted or controlled for OAC, that is, vitamin-K-antagonists (VKA, n = 1186) and non-vitamin-K-antagonist-oral-anticoagulants (NOAC, n = 107). Confounding was addressed using propensity score matching, cox regression modeling and multivariate modeling. Main outcomes were occurrence, extent, and timing of HE (>33%/>6 mL) and its association with 3-month functional outcome.ResultsOccurrence of HE was not different after deep versus lobar ICH in patients with non-OAC-ICH (39/356 [11.0%] vs. 36/305 [11.8%], P = 0.73), VKA-ICH (249/681 [36.6%] vs. 183/505 [36.2%], P = 0.91), and NOAC-ICH (21/69 [30.4%] vs. 12/38 [31.6%], P = 0.90). HE extent did not differ after non-OAC-ICH (deep:+59% [40-122] vs. lobar:+74% [37-124], P = 0.65), but both patients with VKA-ICH and NOAC-ICH showed greater HE extent after deep ICH [VKA-ICH, deep: +94% [54-199] vs. lobar: +56% [35-116], P < 0.001; NOAC-ICH, deep: +74% [56-123] vs. lobar: +40% [21-49], P = 0.001). Deep compared to lobar ICH patients had higher HE hazard during first 13.5 h after onset (Hazard ratio [HR]: 1.85 [1.03-3.31], P = 0.04), followed by lower hazard (13.5-26.5 h, HR: 0.46 [0.23-0.89], P = 0.02), and equal hazard thereafter (HR: 0.96 [0.56-1.65], P = 0.89). Odds ratio for unfavorable outcome was higher after HE in deep (4.31 [2.71-6.86], P < 0.001) versus lobar ICH (2.82 [1.71-4.66], P < 0.001), and only significant after small-medium (1st volume-quarter, deep: 3.09 [1.52-6.29], P < 0.01; lobar: 3.86 [1.35-11.04], P = 0.01) as opposed to large-sized ICH (4th volume-quarter, deep: 1.09 [0.13-9.20], P = 0.94; lobar: 2.24 [0.72-7.04], P = 0.17).InterpretationHE occurrence does not differ among deep and lobar ICH. However, compared to lobar ICH, HE after deep ICH is of greater extent in OAC-ICH, occurs earlier and may be of greater clinical relevance. Overall, clinical significance is more apparent after small-medium compared to large-sized bleedings.

Project description:BackgroundIntraventricular hemorrhage (IVH) after intracerebral hemorrhage (ICH) is a strong independent predictor of poor outcomes. Although the location and volume of ICH are associated with IVH, our knowledge concerning the mechanism of IVH after ICH is still limited. This study aimed to investigate the relationship between hematoma morphology and IVH in patients with supratentorial deep ICH.MethodsWe retrospectively analyzed adult patients (aged ≥18 years) with spontaneous supratentorial deep ICH who underwent computed tomography (CT) within 48 h after ICH symptom onset in Peking University First Hospital between January 2017 and August 2022. We collected the clinical and imaging data of the patients and assessed hematoma morphology using several quantitative radiological parameters including hematoma volume, sphericity index, A/B ratio (A: the largest area of hematoma; B: the largest diameter 90° to A on the same slice), and our newly proposed largest diameter-midline angle (LMA). Multivariable logistic regression analysis was used to analyze the relationship between these parameters and the presence of IVH on the initial CT scan.ResultsAmong 114 patients with spontaneous supratentorial deep ICH, 41 (36.0%) had IVH. In patients with IVH, the sphericity index was lower than that in individuals without IVH, while the LMA was larger. Multivariate logistic regression analysis showed that sphericity index [0.1-unit odds ratio (OR) =0.252; 95% CI: 0.089-0.709; P=0.009] and the LMA (10-unit OR =1.281; 95% CI: 1.007-1.630; P=0.04) were independently associated with the presence of IVH in patients with supratentorial deep ICH. Univariate analyses showed that hematoma volume, A/B ratio, sphericity index, and the LMA were significantly associated with poor outcomes at discharge.ConclusionsTwo quantitative parameters of hematoma morphology, sphericity index and the LMA, were significantly associated with the presence of IVH in patients with supratentorial deep ICH. Further prospective studies with larger sample sizes are needed to validate our results.

Project description:BACKGROUND:Hematoma expansion (HE) after intracerebral hemorrhage (ICH) is associated with worse outcome. Lobar ICHs are known to have better outcomes compared to deep ICH; however, it is unclear whether there are HE differences between these locations. We sought to investigate the hypothesis that lobar ICH has less HE compared to deep ICH. METHODS:Primary ICH patients admitted between 2009 and 2016 were included in a prospective single-center ICH cohort study. Patients with preceding anticoagulant use, coagulopathy on admission labs, or presenting after 24?h from symptom onset were excluded. Lobar and deep ICH patients with baseline and follow-up computed tomography (CT) (within 24?h of admission CT) were evaluated. HE was defined primarily as relative growth >?33% given expected baseline hematoma volume differences between locations. Other commonly utilized definitions of HE: >?6 mL, and >?33% or >?6 mL, were additionally assessed. Multivariable logistic regression was used to assess the association of ICH location with HE while adjusting for previously identified covariates of HE. RESULTS:There were 59 lobar and 143 deep ICH patients analyzed. Lobar ICH patients had significantly larger baseline hematoma volumes, lower admission systolic blood pressure, and longer times to admission CT compared to deep ICH. Multivariable logistic regression revealed an association of lobar ICH with lower odds of HE (>?33%) [odds ratio (OR) 0.32; 95% confidence interval (CI) 0.11-0.93; p?=?0.04] compared to deep ICH after adjusting for baseline ICH volume, blood pressure, and time to CT. Secondary analysis did not identify an association of lobar ICH with HE defined as >?6 mL (adjusted OR 1.44; 95% CI 0.59-3.50; p?=?0.41) or >?33% or >?6 mL (adjusted OR 0.71; 95% CI 0.29-1.70; p?=?0.44). CONCLUSION:We identified less HE in lobar compared to deep ICH. The use of absolute growth thresholds in defining HE may be limited when assessing groups with largely different baseline hematoma sizes. Further study is required to replicate our findings and investigate mechanisms for HE differences between lobar and deep ICH locations.

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Recombinant CCL17 Enhances Hematoma Resolution and Activation of CCR4/ERK/Nrf2/CD163 Signaling Pathway After Intracerebral Hemorrhage in Mice.

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