Dynamic Brain Lipid Profiles Modulate Microglial Lipid Droplet Accumulation and Inflammation Under Ischemic Conditions in Mice.

Microglia are critically involved in post-stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation in microglia results in a dysfunctional and pro-inflammatory state in the aged brain and worsens the outcome of neuroinflammatory and neurodegenerative diseases. However, the role of LD-rich microglia (LDRM) under stroke conditions is unknown. Using in vitro and in vivo stroke models, herein accumulation patterns of microglial LD and their corresponding microglial inflammatory signaling cascades are studied. Interactions between temporal and spatial dynamics of lipid profiles and microglial phenotypes in different post-stroke brain regions are found. Hence, microglia display enhanced levels of LD accumulation and elevated perilipin 2 (PLIN2) expression patterns when exposed to hypoxia or stroke. Such LDRM exhibit high levels of TNF-α, IL-6, and IL-1ß as well as a pro-inflammatory phenotype and differentially expressed lipid metabolism-related genes. These post-ischemic alterations result in distinct lipid profiles with spatial and temporal dynamics, especially with regard to cholesteryl ester and triacylglycerol levels, further exacerbating post-ischemic inflammation. The present study sheds new light on the dynamic changes of brain lipid profiles and aggregation patterns of LD in microglia exposed to ischemia, demonstrating a mutual mechanism between microglial phenotype and function, which contributes to progression of brain injury.

Extracellular vesicles as carriers for noncoding RNA-based regulation of macrophage/microglia polarization: an emerging candidate regulator for lung and traumatic brain injuries.

Macrophage/microglia function as immune defense and homeostatic cells that originate from bone marrow progenitor cells. Macrophage/microglia activation is historically divided into proinflammatory M1 or anti-inflammatory M2 states based on intracellular dynamics and protein production. The polarization of macrophages/microglia involves a pivotal impact in modulating the development of inflammatory disorders, namely lung and traumatic brain injuries. Recent evidence indicates shared signaling pathways in lung and traumatic brain injuries, regulated through non-coding RNAs (ncRNAs) loaded into extracellular vesicles (EVs). This packaging protects ncRNAs from degradation. These vesicles are subcellular components released through a paracellular mechanism, constituting a group of nanoparticles that involve exosomes, microvesicles, and apoptotic bodies. EVs are characterized by a double-layered membrane and are abound with proteins, nucleic acids, and other bioactive compounds. ncRNAs are RNA molecules with functional roles, despite their absence of coding capacity. They actively participate in the regulation of mRNA expression and function through various mechanisms. Recent studies pointed out that selective packaging of ncRNAs into EVs plays a role in modulating distinct facets of macrophage/microglia polarization, under conditions of lung and traumatic brain injuries. This study will explore the latest findings regarding the role of EVs in the progression of lung and traumatic brain injuries, with a specific focus on the involvement of ncRNAs within these vesicles. The conclusion of this review will emphasize the clinical opportunities presented by EV-ncRNAs, underscoring their potential functions as both biomarkers and targets for therapeutic interventions.

Inflammation-associated D-dimer predicts neurological outcome of recent small subcortical infarct: A prospective clinical and laboratory study.

OBJECTIVE: Elevated level of D-Dimer often indicates a worse prognosis in cerebral infarction. However, there is limited research on this impact within recent small subcortical infarction (RSSI). We aim to explore the role of inflammation and the total magnetic resonance imaging (MRI) burden of cerebral small vessel disease (cSVD) in this process. METHODS: 384 RSSI patients and 189 matched healthy controls were strictly registered in the current research. We evaluated short-term and long-term outcomes by measuring the percentage of the National Institutes of Health Stroke Scale (NIHSS) improvement and the modified Rankin Scale (mRS) at 3 months, respectively. We also assessed the chronic, sustained brain damage associated with cSVD using the total MRI burden and confirmed the relationship between prognosis and the total MRI burden of cSVD. Furthermore, we explored the associations between D-dimer and C-reactive protein (CRP) levels with NIHSS improvement and mRS at 3 months, as well as their relationships with both the total MRI burden of cSVD and its 4 imaging features. RESULTS: Both NIHSS improvement and the mRS at 3 months were found to be correlated with the total MRI burden of cSVD. Higher D-dimer and CRP levels showed a linear correlation, indicating worse prognosis and a higher total MRI burden of cSVD. The four imaging features of the total MRI burden of cSVD did not exhibit entirely consistent patterns when exploring their correlations with prognosis and laboratory indicators. CONCLUSION: Inflammation-associated D-dimer predicts neurological outcomes in patients with recent small subcortical infarct, and reflects a more severe total MRI burden of cSVD.

TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-ß1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-ß1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-ß1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases.

Increased level of FAM19A5 is associated with cerebral small vessel disease and leads to a better outcome.

Objective: FAM19A5 plays an essential role in the development and acute or chronic inflammation of the central nervous system. The present study aimed to explore the association between FAM19A5 and cerebral small vessel disease (cSVD). Methods: A total of 344 recent small subcortical infarct (RSSI) patients and 265 healthy controls were included in this study. The difference in the FAM19A5 level between the two groups was compared and the correlation between FAM19A5 and cerebral infarction volume was analyzed. Also, the association between FAM19A5 and the total magnetic resonance imaging (MRI) burden with its imaging characteristics was explored. Moreover, the correspondence of FAM19A5 with the outcome was assessed via Δ National Institutes of Health Stroke Scale score (NIHSS) and the percentage of NIHSS improvement. Results: FAM19A5 was highly expressed in the RSSI group (P = 0.023), showing a positive correlation with cerebral infarction volume (P < 0.01). It was positively correlated with total MRI cSVD burden (P < 0.001) and reflected the severity of white matter hyperintensity (WMH) (P < 0.01) and enlarged perivascular space (EPVS) (P < 0.01), but did not show any association with cerebral microbleed (CMB) and lacune. Moreover, FAM19A5 suggested a larger Δ NIHSS (P = 0.021) and NIHSS improvement percentage (P = 0.007). Conclusion: Serum FAM19A5 was increased in RSSI and positively correlated with the infarct volume. It also reflects the total MRI burden of cSVD, of which the imaging characteristics are positively correlated with WMH and EPVS. In addition, higher FAM19A5 levels reflect better outcomes in RSSI patients.

Plasma chromogranin A levels are associated with acute ischemic stroke with anterior circulation large vessel occlusion.

BACKGROUND AND AIMS: To investigate the relationship between chromogranin A (CgA) levels and acute ischemic stroke (AIS), especially anterior circulation large vessel occlusion (LVO). METHODS AND RESULTS: 587 subjects were included in this study, including 205 AIS patients with anterior circulation LVO and 205 nonocclusive patients, as well as 177 healthy controls. On admission, plasma CgA levels were measured and neurological deficits were assessed by the NIH Stroke Scale. Outcomes were assessed by the modified Rankin Scale at 3 months. The predictive properties of CgA were evaluated by receiver operating characteristic (ROC) curve analysis. Binary logistic analysis assessed the association of CgA levels and AIS or anterior circulation LVO. AIS patients had lower CgA levels than health controls (p < 0.001). Anterior circulation LVO patients had lower CgA levels than nonocclusive patients (p < 0.001). The area under the ROC curve of plasma CgA levels in predicting anterior circulation LVO from AIS was 0.744 and the optimal cutoff value was 15.49 ng/mL with a Youden value of 0.332. Logistic analysis showed that CgA ≤15.49 ng/mL remained an independent risk factor for anterior circulation LVO after adjusting for related factors (OR = 6.519, 95% CI: 3.790-11.214, p < 0.001). CgA was an independent protective factor for mild stroke and good prognosis (p = 0.009, p = 0.005); however, the association disappeared after adjusting for occlusion (p = 0.768, p = 0.335). CONCLUSION: CgA levels were lower in AIS patients, especially in anterior circulation LVO patients. Lower CgA levels are potential biomarker for anterior circulation LVO, and they may indicate good prognosis at 3 months in AIS.