ChemR23 signaling ameliorates cognitive impairments in diabetic mice via dampening oxidative stress and NLRP3 inflammasome activation.

Diabetes mellitus is associated with cognitive impairment characterized by memory loss and cognitive inflexibility. Recent studies have revealed that ChemR23 is implicated in both diabetes mellitus and Alzheimer's disease. However, the impact of ChemR23 on diabetes-associated cognitive impairment remains elusive. In this study, we explored the longitudinal changes of ChemR23 expression and cognitive function in STZ-induced type 1 diabetic mice and leptin receptor knockout type 2 diabetic mice at different ages. We also treated diabetic mice with ChemR23 agonists RvE1 or chemerin-9 to explore whether ChemR23 activation could alleviate diabetes-associated cognitive impairment. The underlying mechanism was further investigated in diabetic mice with genetic deletion of ChemR23. The results showed that ChemR23 expression was decreased along with aging and the progression of diabetes, suggesting that abnormal ChemR23 signaling may be involved in diabetes-associated cognitive impairment. Administration of RvE1 or chemerin-9 ameliorated oxidative stress and inhibited NLRP3 inflammasome activation through Nrf2/TXNIP pathway, and ultimately alleviated cognitive impairment in diabetic mice. Depletion of ChemR23 in diabetic mice abolished the beneficial effects of RvE1 and chemerin-9, and exacerbated cognitive impairment via increasing oxidative stress and activating NLRP3 inflammasome. Collectively, our data highlight the crucial role of ChemR23 signaling in diabetes-associated cognitive impairment via regulating oxidative stress and NLRP3 inflammasome, and targeting ChemR23 may serve as a promising novel strategy for the treatment of diabetes-associated cognitive impairment.

Resolution of inflammation is disturbed in acute ischemic stroke with diabetes mellitus and rescued by resolvin D2 treatment.

BACKGROUND: Inflammation plays an important role in diabetes mellitus (DM)-related acute ischemic stroke (AIS). The mechanisms of un-resolved inflammation in DM-related AIS are not fully understood. Specialized pro-resolving mediators (SPMs) are key regulators that promote resolution of inflammation. We aimed to examine resolution function in patients with AIS complicated with DM, and explore potential treatment effects of one of the SPMs, resolvin D2 (RvD2) ex vivo and in vivo. METHODS: Cultured human macrophages, which were derived from peripheral blood mononuclear cells of AIS and none-AIS patients with or without DM, were stimulated with oxidized-low density lipoprotein (ox-LDL). Levels of SPMs and inflammatory markers were analysed, and RvD2 treatment effects were evaluated in these cells. For experiments in vivo, challenges with high fat diet and low-dose streptozotocin (STZ) were used to induce DM in C57BL/6J mice. AIS model was established by permanent middle cerebral artery occlusion (pMCAO) followed by intra-cerebroventricular injection of RvD2. RESULTS: Compared with macrophages of AIS patients without DM, the ratios of SPMs to leukotriene B4 (LTB4) were decreased in AIS patients with DM, accompanied by reduced expression of SPM synthesis enzyme, 15-lipoxygenase-1. Moreover, the levels of pro-inflammatory pathway markers were increased, and the macrophages were skewed to M1 polarization in AIS patients with DM. In mice, treatment with RvD2 ameliorated pMCAO-induced brain injury, neurological dysfunction, and inflammatory response. Furthermore, RvD2 rescued resolution of inflammation by promoting macrophage/microglia polarization to pro-resolving M2 phenotype ex vivo and in vivo. CONCLUSIONS: Our data demonstrate resolution of inflammation is impaired by DM in AIS patients, implicating a novel mechanism of un-resolved inflammation in DM-related AIS. Furthermore, RvD2 promotes inflammation resolution in macrophages/microglia and protects DM-related AIS, and may thus serve as a novel therapeutic target.

Plasma Resolvin D2 to Leukotriene B4 Ratio Is Reduced in Diabetic Patients with Ischemic Stroke and Related to Prognosis.

BACKGROUND: Diabetes mellitus (DM) aggravates symptoms and prognosis of acute ischemic stroke (AIS), and inflammation plays an important role therein. Resolvin D2 (RvD2) is one of the specialized pro-resolving mediators (SPMs), while leukotriene B4 (LTB4) is a classic proinflammatory mediator. The ratio of RvD2 to LTB4 is an index of pro-resolving/proinflammatory balance. We aim to explore the role of RvD2/LTB4 ratio in ischemic stroke complicated with DM. METHODS: The plasma levels of RvD2 and LTB4 were analyzed by enzyme immunoassay in stroke patients with DM (DM + AIS group) or without DM (nonDM+AIS group). Patients were followed up at 90 days after stroke onset, and modified Rankin Score (mRS) was assessed. The association of RvD2/LTB4 ratio with stroke severity and prognosis was also analyzed. RESULTS: The plasma levels of RvD2 were positively correlated to LTB4. The RvD2/LTB4 ratio in DM + AIS group was lower than that in the nonDM+AIS group. No correlation was found between the RvD2/LTB4 ratio and infarct size or NIHSS score. The RvD2/LTB4 ratio at baseline was significantly lower in the poor prognosis group (mRS ≥ 3) than that in the good prognosis group (mRS ≤ 2). CONCLUSIONS: Our study indicated that the balance between pro-resolving and proinflammatory mediators was impaired by diabetes in ischemic stroke. The RvD2/LTB4 ratio may serve as a biomarker of prognosis for ischemic stroke.

Role of polyunsaturated fatty acids in ischemic stroke - A perspective of specialized pro-resolving mediators.

Polyunsaturated fatty acids (PUFAs) have been proposed as beneficial for cardiovascular health. However, results from both epidemiological studies and clinical trials have been inconsistent, whereas most of the animal studies showed promising benefits of PUFAs in the prevention and treatment of ischemic stroke. In recent years, it has become clear that PUFAs are metabolized into various types of bioactive derivatives, including the specialized pro-resolving mediators (SPMs). SPMs exert multiple biofunctions, such as to limit excessive inflammatory responses, regulate lipid metabolism and immune cell functions, decrease production of pro-inflammatory factors, increase anti-inflammatory mediators, as well as to promote tissue repair and homeostasis. Inflammation has been recognised as a key contributor to the pathophysiology of acute ischemic stroke. Owing to their potent pro-resolving actions, SPMs are potential for development of novel anti-stroke therapy. In this review, we will summarize current knowledge of epidemiological studies, basic research and clinical trials concerning PUFAs in stroke prevention and treatment, with special attention to SPMs as the unsung heroes behind PUFAs.

Reduced Levels of Plasma Lipoxin A4 Are Associated with Post-Stroke Cognitive Impairment.

BACKGROUND: Specialized pro-resolving mediators (SPMs) are bioactive lipids derived from n-3 and n-6 polyunsaturated fatty acids. SPMs promote resolution of inflammation and are reduced in Alzheimer's disease. It is unknown whether SPMs are associated with post-stroke cognitive impairment (PSCI). OBJECTIVE: In the present report, we aimed to study the levels of SPMs in PSCI patients in the acute phase of ischemic stroke. METHODS: Levels of SPMs in the plasma from 36 patients with PSCI and 33 patients with post-stroke non-cognitive impairment (PSNCI) were measured by enzyme immunoassay. RESULTS: We found that levels of the SPM lipoxin A4 (LXA4) were significantly reduced in PSCI patients compared with PSNCI patients. Interestingly, the LXA4 levels were positively correlated with Mini-Mental State Examination scores, but not with the National Institutes of Health Stroke Scale scores. Such alteration and correlation were not found in any of the other SPMs analyzed, i.e., including resolvin D1, resolvin D2, and maresin 1. CONCLUSION: We conclude that the plasma levels of LXA4 were reduced in PSCI patents in the acute phase of ischemic stroke and were correlated to cognitive function.