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Öğe Dynamic brain lipid profiles modulate microglial lipid droplet accumulation and inflammation under ischemic conditions in mice(2024) Wei, Wei; Lattau, Seyed Siyawasch Justus; Xin, Wenqiang; Pan, Yongli; Tatenhorst, Lars; Zhang, Lin; Doeppner, Thorsten RolandMicroglia 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-1β 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.Öğe Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-beta/Smad2/3 pathway(Springer Nature, 2021) Zhang, Lin; Wei, Wei; Ai, Xiaoyu; Kılıç, Ertuğrul; Hermann, Dirk M.; Venkataramani, Vivek; Baehr, Mathias; Doeppner, Thorsten R.Systemic transplantation of oxygen-glucose deprivation (OGD)-preconditioned primary microglia enhances neurological recovery in rodent stroke models, albeit the underlying mechanisms have not been sufficiently addressed. Herein, we analyzed whether or not extracellular vesicles (EVs) derived from such microglia are the biological mediators of these observations and which signaling pathways are involved in the process. Exposing bEnd.3 endothelial cells (ECs) and primary cortical neurons to OGD, the impact of EVs from OGD-preconditioned microglia on angiogenesis and neuronal apoptosis by the tube formation assay and TUNEL staining was assessed. Under these conditions, EV treatment stimulated both angiogenesis and tube formation in ECs and repressed neuronal cell injury. Characterizing microglia EVs by means of Western blot analysis and other techniques revealed these EVs to be rich in TGF-beta 1. The latter turned out to be a key compound for the therapeutic potential of microglia EVs, affecting the Smad2/3 pathway in both ECs and neurons. EV infusion in stroke mice confirmed the aforementioned in vitro results, demonstrating an activation of the TGF-beta/Smad2/3 signaling pathway within the ischemic brain. Furthermore, enriched TGF-beta 1 in EVs secreted from OGD-preconditioned microglia stimulated M2 polarization of residing microglia within the ischemic cerebral environment, which may contribute to a regulation of an early inflammatory response in postischemic hemispheres. These observations are not only interesting from the mechanistic point of view but have an immediate therapeutic implication as well, since stroke mice treated with such EVs displayed a better functional recovery in the behavioral test analyses. Hence, the present findings suggest a new way of action of EVs derived from OGD-preconditioned microglia by regulating the TGF-beta/Smad2/3 pathway in order to promote tissue regeneration and neurological recovery in stroke mice.Öğe Inhibition of fatty acid synthesis aggravates brain injury, reduces blood-brain barrier integrity and impairs neurological recovery in a murine stroke model(Frontiers Media SA, 2021) Janssen, Lisa; Ai, Xiaoyu; Zheng, Xuan; Wei, Wei; Çağlayan, Ahmet Burak; Kılıç, Ertuğrul; Wang, Ya-chao; Hermann, Dirk M.; Venkataramani, Vivek; Baehr, Mathias; Doeppner, Thorsten R.Inhibition of fatty acid synthesis (FAS) stimulates tumor cell death and reduces angiogenesis. When SH-SY5Y cells or primary neurons are exposed to hypoxia only, inhibition of FAS yields significantly enhanced cell injury. The pathophysiology of stroke, however, is not only restricted to hypoxia but also includes reoxygenation injury. Hence, an oxygen-glucose-deprivation (OGD) model with subsequent reoxygenation in both SH-SY5Y cells and primary neurons as well as a murine stroke model were used herein in order to study the role of FAS inhibition and its underlying mechanisms. SH-SY5Y cells and cortical neurons exposed to 10 h of OGD and 24 h of reoxygenation displayed prominent cell death when treated with the Acetyl-CoA carboxylase inhibitor TOFA or the fatty acid synthase inhibitor cerulenin. Such FAS inhibition reduced the reduction potential of these cells, as indicated by increased NADH(2)(+)/NAD(+) ratios under both in vitro and in vivo stroke conditions. As observed in the OGD model, FAS inhibition also resulted in increased cell death in the stroke model. Stroke mice treated with cerulenin did not only display increased brain injury but also showed reduced neurological recovery during the observation period of 4 weeks. Interestingly, cerulenin treatment enhanced endothelial cell leakage, reduced transcellular electrical resistance (TER) of the endothelium and contributed to poststroke blood-brain barrier (BBB) breakdown. The latter was a consequence of the activated NF-kappa B pathway, stimulating MMP-9 and ABCB1 transporter activity on the luminal side of the endothelium. In conclusion, FAS inhibition aggravated poststroke brain injury as consequence of BBB breakdown and NF-kappa B-dependent inflammation.Öğe Knockdown of NEAT1 prevents post-stroke lipid droplet agglomeration in microglia by regulating autophagy(Springer Science and Business Media Deutschland GmbH, 2024) Pan, Yongli; Xin, Wenqiang; Wei, Wei; Tatenhorst, Lars; Graf, Irina; Popa-Wagner, Aurel; Gerner, Stefan T.; Huber, Sabine E.; Kılıç, Ertuğrul; Hermann, Dirk M.; Bähr, Mathias; Huttner, Hagen B.; Doeppner, Thorsten RolandBackground: Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration and autophagy in multiple neurological disorders. However, knowledge as to how NEAT1 modulates the formation of LD and associated signaling pathways is limited. Methods: In this study, primary microglia were isolated from newborn mice and exposed to oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, an antisense oligonucleotide (ASO) was adopted to silence NEAT1 under in vitro conditions. Studying NEAT1-dependent interactions with regard to autophagy and LD agglomeration under hypoxic conditions, the inhibitor and activator of autophagy 3-methyladenine (3-MA) and rapamycin (RAPA) were used, respectively. In a preclinical stroke model, mice received intraventricular injections of ASO NEAT1 or control vectors in order to yield NEAT1 knockdown. Analysis of readout parameters included qRT-PCR, immunofluorescence, western blot assays, and behavioral tests. Results: Microglia exposed to OGD/R displayed a temporal pattern of NEAT1 expression, peaking at four hours of hypoxia followed by six hours of reoxygenation. After effectively silencing NEAT1, LD formation and autophagy-related proteins were significantly repressed in hypoxic microglia. Stimulating autophagy in ASO NEAT1 microglia under OGD/R conditions by means of RAPA reversed the downregulation of LD agglomeration and perilipin 2 (PLIN2) expression. On the contrary, application of 3-MA promoted repression of both LD agglomeration and expression of the LD-associated protein PLIN2. Under in vivo conditions, NEAT1 was significantly increased in mice at 24 h post-stroke. Knockdown of NEAT1 significantly alleviated LD agglomeration and inhibited autophagy, resulting in improved cerebral perfusion, reduced brain injury and increased neurological recovery. Conclusion: NEAT1 is a key player of LD agglomeration and autophagy stimulation, and NEAT1 knockdown provides a promising therapeutic value against stroke. Graphical abstract: [Figure not available: see fulltext.].Öğe Management of granulomatous lobular mastitis: an international multidisciplinary consensus (2021 edition)(BMC, 2022) Yuan, Qian-Qian; Xiao, Shu-Xuan; Farouk, Omar; Du, Yu-Tang; Sheybani, Fereshte; Tan, Qing Ting; Akbulut, Sami; Çetin, Kenan; Alikhassi, Afsaneh; Yaghan, Rami Jalal; Durur Subaşı, Irmak; Altıntoprak, Fatih; Eom, Tae Ik; Alper, Fatih; Hasbahçeci, Mustafa; Martinez-Ramos, David; Öztekin, Pelin Seher; Kwong, Ava; Pluguez-Turull, Cedric W.; Brownson, Kirstyn E.; Chandanwale, Shirish; Habibi, Mehran; Lan, Liu-Yi; Zhou, Rui; Zeng, Xian-Tao; Bai, Jiao; Bai, Jun-Wen; Chen, Qiong-Rong; Chen, Xing; Zha, Xiao-Ming; Dai, Wen-Jie; Dai, Zhi-Jun; Feng, Qin-Yu; Gao, Qing-Jun; Gao, Run-Fang; Han, Bao-San; Hou, Jin-Xuan; Hou, Wei; Liao, Hai-Ying; Luo, Hong; Liu, Zheng-Ren; Lu, Jing-Hua; Luo, Bin; Ma, Xiao-Peng; Qian, Jun; Qin, Jian-Yong; Wei, Wei; Wei, Gang; Xu, Li-Ying; Xue, Hui-Chao; Yang, Hua-Wei; Yang, Wei-Ge; Zhang, Chao-Jie; Zhang, Fan; Zhang, Guan-Xin; Zhang, Shao-Kun; Zhang, Shu-Qun; Zhang, Ye-Qiang; Zhang, Yue-Peng; Zhang, Sheng-Chu; Zhao, Dai-Wei; Zheng, Xiang-Min; Zheng, Le-Wei; Xu, Gao-Ran; Zhou, Wen-Bo; Wu, Gao-SongGranulomatous lobular mastitis (GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions, etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology. The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidence-based consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.Öğe Management of granulomatous lobular mastitis: An international multidisciplinary consensus (2021 edition) (vol 9, 20, 2022)(BMC, 2022) Yuan, Qian-Qian; Xiao, Shu-Yuan; Farouk, Omar; Du, Yu-Tang; Sheybani, Fereshte; Tan, Qing Ting; Akbulut, Sami; Çetin, Kenan; Alikhassi, Afsaneh; Yaghan, Rami Jalal; Durur Subaşı, Irmak; Altıntoprak, Fatih; Eom, Tae Ik; Alper, Fatih; Hasbahçeci, Mustafa; Martinez-Ramos, David; Öztekin, Pelin Seher; Kwong, Ava; Pluguez-Turull, Cedric W.; Brownson, Kirstyn E.; Chandanwale, Shirish; Habibi, Mehran; Lan, Liu-Yi; Zhou, Rui; Zeng, Xian-Tao; Bai, Jiao; Bai, Jun-Wen; Chen, Qiong-Rong; Chen, Xing; Zha, Xiao-Ming; Dai, Wen-Jie; Dai, Zhi-Jun; Feng, Qin-Yu; Gao, Qing-Jun; Gao, Run-Fang; Han, Bao-San; Hou, Jin-Xuan; Hou, Wei; Liao, Hai-Ying; Luo, Hong; Liu, Zheng-Ren; Lu, Jing-Hua; Luo, Bin; Ma, Xiao-Peng; Qian, Jun; Qin, Jian-Yong; Wei, Wei; Wei, Gang; Xu, Li-Ying; Xue, Hui-Chao; Yang, Hua-Wei; Yang, Wei-Ge; Zhang, Chao-Jie; Zhang, Fan; Zhang, Guan-Xin; Zhang, Shao-Kun; Zhang, Shu-Qun; Zhang, Ye-Qiang; Zhang, Yue-Peng; Zhang, Sheng-Chu; Zhao, Dai-Wei; Zheng, Xiang-Min; Zheng, Le-Wei; Xu, Gao-Ran; Zhou, Wen-Bo; Wu, Gao-Song[Abstract Not Available]Öğe Preconditioned extracellular vesicles from hypoxic microglia reduce poststroke AQP4 depolarization, disturbed cerebrospinal fluid flow, astrogliosis, and neuroinflammation(NLM (Medline), 2023) Xin, Wenqiang; Pan, Yongli; Wei, Wei; Tatenhorst, Lars; Graf, Irina; Popa-Wagner, Aurel; Gerner, Stefan T.; Huber, Sabine; Kılıç, Ertuğrul; Hermann, Dirk M.; Bähr, Mathias; Huttner, Hagen B.; Doeppner, Thorsten RolandBackground: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release.Öğe TGF-?1 decreases microglia-mediated neuroinflammation and lipid droplet accumulation in an in vitro stroke model(Multidisciplinary Digital Publishing Institute (MDPI), 2023) Xin, Wenqiang; Pan, Yongli; Wei, Wei; Gerner, Stefan T.; Huber, Sabine; Juenemann, Martin; Butz, Marius; Baehr, Mathias; Huttner, Hagen B.; Doeppner, Thorsten RolandHypoxia triggers reactive microglial inflammation and lipid droplet (LD) accumulation under stroke conditions, although the mutual interactions between these two processes are insufficiently understood. Hence, the involvement of transforming growth factor (TGF)-beta 1 in inflammation and LD accumulation in cultured microglia exposed to hypoxia were analyzed herein. Primary microglia were exposed to oxygen-glucose deprivation (OGD) injury and lipopolysaccharide (LPS) stimulation. For analyzing the role of TGF-beta 1 patterns under such conditions, a TGF-beta 1 siRNA and an exogenous recombinant TGF-beta 1 protein were employed. Further studies applied Triacsin C, an inhibitor of LD formation, in order to directly assess the impact of LD formation on the modulation of inflammation. To assess mutual microglia-to-neuron interactions, a co-culture model of these cells was established. Upon OGD exposure, microglial TGF-beta 1 levels were significantly increased, whereas LPS stimulation yielded decreased levels. Elevating TGF-beta 1 expression proved highly effective in suppressing inflammation and reducing LD accumulation in microglia exposed to LPS. Conversely, inhibition of TGF-beta 1 led to the promotion of microglial cell inflammation and an increase in LD accumulation in microglia exposed to OGD. Employing the LD formation inhibitor Triacsin C, in turn, polarized microglia towards an anti-inflammatory phenotype. Such modulation of both microglial TGF-beta 1 and LD levels significantly affected the resistance of co-cultured neurons. This study provides novel insights by demonstrating that TGF-beta 1 plays a protective role against microglia-mediated neuroinflammation through the suppression of LD accumulation. These findings offer a fresh perspective on stroke treatment, suggesting the potential of targeting this pathway for therapeutic interventions.Öğe TREM2 regulates microglial lipid droplet formation and represses post-ischemic brain injury(Elsevier Masson s.r.l., 2024) Wei, Wei; Zhang, Lin; Xin, Wenqiang; Pan, Yongli; Tatenhorst, Lars; Hao, Zhongnan; Gerner, Stefan T.; Huber, Sabine; Juenemann, Martin; Doeppner, Thorsten RolandTriggering 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-?1/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-?1 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-?1/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.
