查找使用阿拉丁产品的科研文献

C5aR1+ macrophages are involved in the progression of endometriosis

Chen Xi,Zuo Wei-Wen,Zhang Guo-Dong,Xu Cong-Jian

Objective: Immune dysfunction plays an important role in the pathogenesis of endometriosis. C5a, a by-product of complement activation, binds to its receptor (C5a receptor 1, C5aR1) in various cells, including macrophages. The combination of C5a and C5aR1 in macrophages induces M2 polarization. There is no consistent conclusion regarding macrophage polarization status and its participation in the pathogenesis of endometriosis. Methods: We analyzed the expression of C5aR1 and the immunophenotype of macrophages in samples from patients with endometriosis using immunohistochemistry and flow cytometry. We tested the equivalent item in a mouse model and the THP-1 cell line in vivo and in vitro . Single-cell RNA sequencing (scRNA-seq) from the Gene Expression Omnibus (GEO, GSE213216) was used to investigate the phenotype and function of C5aR1 + macrophages. Results: The infiltration of C5aR1 + macrophages was associated with the severity of endometriosis. C5aR1 + macrophages polarized more toward the M2 phenotype and transformed into an immunosuppressive state. Inhibiting C5aR1 using PMX-53 decreased the expression of C5aR1 + macrophages and reduced their polarization to the M2 phenotype, consequently shrinking lesion size in a mouse model. Conclusion: Our study emphasizes the importance of C5aR1 and the macrophage phenotype in the pathogenesis of endometriosis. We propose PMX-53 as a potential therapeutic agent for endometriosis.

Engineered renal-targeting nanozyme achieves sequential treatment of AKI through ROS clearance and immune modulation

Zhiwen Wang,Yue Xie,Mingcun Hu,Min Yang,Xingjian Zou,Chun Zhang

Effective countermeasures for acute kidney injury (AKI) remain unsatisfactory. During AKI progression, the timely and appropriate transition of macrophages from pro-inflammatory to anti-inflammatory states is critical for resolving acute inflammation and promoting tissue repair. Timely clearing of excess reactive oxygen species (ROS) and promotion of M2 polarization of macrophages are key determinants of AKI progression. Accordingly, we report an engineered renal-targeting nanozyme constructed from a novel two-dimensional nanomaterial, MXene nanosheets, via surface conjugation of the anticomplement component 5a aptamer (ac5a-Apt) and magnesium ions (Mg 2 + ). After AKI, the engineered nanozyme can not only target the kidneys but also navigates to inflammatory areas under the guidance of the ac5a-Apt, clear excessive ROS, inhibits the C5a-C5aR complement system activation and promote M2 polarization of macrophages. Importantly, after MXene reacts with ROS and degrades, the surface-loaded Mg 2+ is released, further suppressing the MAPK/ NF-κB signaling pathway to achieve sequential therapy. The engineered renal-targeting nanozyme offers a novel strategy based on ROS clearance and immune modulation for sequential AKI treatment.

Butyrate protects against MRSA pneumonia via regulating gut-lung microbiota and alveolar macrophage M2 polarization

Yan Zhao,Haoming Sun,Yiwei Chen,Qiang Niu,Yiting Dong,Mei Li,Ye Yuan,Xiaojun Yang,Qingzhu Sun

Macrophages alternatively activated by endometriosis-exosomes contribute to the development of lesions in mice

Sun Huihui,Li Dong,Yuan Ming,Li Qiuju,Zhen Qianwei,Li Ni,Wang Guoyun

STUDY QUESTIONDo exosomes play a role in the pathogenesis of endometriosis in a murine model?SUMMARY ANSWERExosomes from endometriosis (EMS) can alternatively activate macrophages and thus contribute to the development of lesions in mice.WHAT IS KNOWN ALREADYThe pathogenesis of endometriosis, an inflammatory disease, possibly involves peritoneal macrophages. Exosomes are recognized as a new communicator among cells and a key modulator in several inflammatory diseases.STUDY DESIGN, SIZE, DURATIONWe performed in vitr and in vivo experiments to demonstrate the role of exosomes in modulating macrophages. RAW264.7 cells (macrophages) were used to examine the effects of exosomes on macrophages in vitro. An experiment was also conducted in vivo, as follows. Fifty C57BL/6 female mice were randomly allocated to five control and five experimental groups (n = 5/group). The experimental group was injected i.p. with EMS-exosomes derived from eutopic stromal cells, starting on Day-7 then every day for 1 week. The control group received CON-exosomes from mice without endometriosis. Peritoneal macrophages were assessed over the next 6 days. On Day 0, all mice were injected i.p. with endometrium to establish the endometriosis model. On Day 14, all mice were sacrificed, ectopic lesions were counted and measured.PARTICIPANTS/MATERIALS, SETTING, METHODSExosomes were isolated from endometrial stromal cells (ESCs) by ultracentrifugation and characterized through transmission electron microscopy, nanoparticle tracking analysis and western blot. After treatment with exosomes, the polarization and phagocytic ability of the macrophages were detected by flow cytometry analysis, immunofluorescent staining and RT-PCR. C57BL/6 mice were utilized to establish an endometriosis model by i.p. injection of endometrial segments.MAIN RESULTS AND THE ROLE OF CHANCEAfter treatment with EMS-exosomes, the macrophages were polarized into an M2-like phenotype and their phagocytic ability decreased (P < 0.05 versus treatment with CON-exosomes). The total weight and volume of the lesions in mice treated with EMS-exosomes significantly increased compared with those in mice treated with CON-exosomes (P < 0.05). The infiltration of M2-like macrophages was enhanced in the EMS-exosome group (P < 0.001 versus treatment with CON-exosomes).LARGE SCALE DATAN/ALIMITATIONS, REASONS FOR CAUTIONDetection of endometriosis following exosome treatment was only performed in a murine endometriosis model. Clinical data and additional mechanism studies must be conducted to understand the role of exosomes in the pathogenesis of endometriosis.WIDER IMPLICATIONS OF THE FINDINGSThis study emphasizes the importance of EMS-exosomes in the pathogenesis of endometriosis. Further investigations on the exosome signaling pathways may contribute to the development of effective treatments for endometriosis.STUDY FUNDING/COMPETING INTEREST(S)This research was supported by grants (Nos. 81571417 and 81771552) from the National Science Foundation of China. The authors report no conflict of interest.

Formononetin ameliorates depression-like behaviors through rebalancing microglia M1/M2 polarization and inhibiting NLRP3 inflammasome: involvement of activating PPARα-mediated autophagy

Peng Shuaijun,Su Pan,Liu Liming,Li Zibo,Liu Yuan,Tian Lei,Bai Ming,Xu Erping,Li Yucheng

Background The dysregulation of neuroinflammation triggered by imbalance of microglia M1/M2 polarization is a key pathogenic factor and closely associated with occurrence of depression. Formononetin (FMN), a natural non-steroidal isoflavonoid, has been confirmed to exhibit remarkable anti-inflammatory efficacy, but the impact of FMN on depression and the underlying antidepressant mechanisms are still not fully understood. This study aimed to investigate whether the antidepressant effect of FMN is involved in modulating microglia polarization, and if so, what are the underlying mechanisms.Methods Lipopolysaccharide (LPS)-induced depressive mice were used to study antidepressant mechanisms of FMN. Microglia cell line BV2 stimulated by LPS was employed to investigate pharmacological mechanisms of FMN. Effects of FMN on neuronal damage were detected by H&E, Nissl and Golgi staining. The efficacy of FMN were evaluated by immunostaining and western blots in vivo and vitro. In addition, molecular docking, luciferase reporter assay, cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) were used to confirm the direct target of FMN.Results Our results showed that FMN significantly reverses depression-like behaviors, alleviates neuroinflammation and neuronal damage, rebalances M1/M2 polarization, inhibits NLRP3 inflammasome and enhances microglial autophagy level in prefrontal cortex of LPS-induced depressive mice. In vitro assays, results unraveled that autophagy inhibitor chloroquine (CQ) blocks effects of FMN on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization. Moreover, PPARα is identified as a direct target of FMN and FMN can activate PPARα-mediated autophagy. Furtherly, combination PPARα agonist (WY14643) with FMN had no significant additive effects on inhibiting NLRP3 inflammasome and rebalancing M1/M2 polarization, whereas PPARα antagonist (GW6471) abrogated these pharmacologic effects of FMN in BV2. Importantly, GW6471 exhibited similar pharmacologic effects to abolish antidepressant effect of FMN in LPS-induced depressive mice.Conclusion Our study firstly demonstrated that FMN can rebalance microglia M1/M2 polarization and inhibit NLRP3 inflammasome, with the involvement of activating PPARα-mediated autophagy to ameliorate depression-like behaviors, which provides a novel view to elucidate antidepressant mechanisms of FMN and also offers a potential therapeutic target for depression.

Astragalus polysacharin inhibits hepatocellular carcinoma-like phenotypes in a murine HCC model through repression of M2 polarization of tumour-associated macrophages

Chun Li,Xin-You Pan,Mingyun Ma,Jun Zhao,Fengda Zhao,Ya-Ping Lv

Context Astragalus polysaccharin (APS), an extract of Astragalus propinquus Schischk, exerts antitumor effects in hepatocellular carcinoma (HCC).Objective This study investigated the mechanism of action of APS in HCC.Materials and methods Tumour-associated macrophages (TAMs) were treated with APS (0, 8, 16 mg/mL) for 24 h. APS (16 mg/mL)-treated TAMs were co-cultured with MHCC97H/Huh7 cells for 24 h. Finally, BALB/c nude mice were divided into PBS, APS (50 mg/kg), APS (100 mg/kg), APS (200 mg/kg) groups: mice were inoculated with Huh7 cells to construct tumour xenograft model, followed by administration of APS (50, 100, 200 mg/kg) or PBS daily for 30 days. Cell proliferation, migration, invasion, tumour growth, macrophage markers and proportions were measured.Results APS 16 mg/mL treatment enhanced the expression of M1 macrophage markers (iNOS, IL-1β and TNF-α) and M1 macrophage proportions, while reducing the expression of M2 macrophage markers (IL-10, Arg-1) and M2 macrophage proportions in TAMs. Moreover, the APS-mediated M1 phenotype of TAMs significantly repressed cell proliferation, migration and invasion of MHCC97H and Huh7 cells. Moreover, APS (50, 100, 200 mg/kg) enhanced M1 macrophage proportions and reduced M2 macrophage proportions in the tumour tissues, and thus inhibited tumour growth of HCC.Discussion and conclusions APS inhibits HCC-like phenotypes in a murine HCC model through repression of M2 polarization of TAMs. This work provides a novel theoretical basis for the application of APS in the clinical treatment of HCC.

Quercetin induces itaconic acid-mediated M1/M2 alveolar macrophages polarization in respiratory syncytial virus infection

Li An,Qianwen Zhai,Keyu Tao,Yingcai Xiong,Weiying Ou,Ziwei Yu,Xingyu Yang,Jianjian Ji,Mengjiang Lu

Background Quercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin's ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive. Purpose This study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection. Methods BALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism. Results Quercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes. Conclusion Our study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.

Biomimetic glycopeptide hydrogel coated PCL/nHA scaffold for enhanced cranial bone regeneration via macrophage M2 polarization-induced osteo-immunomodulation

Yaping Wang,Jingrong Wang,Rui Gao,Xiang Liu,Zujian Feng,Chuangnian Zhang,Pingsheng Huang,Anjie Dong,Deling Kong,Weiwei Wang

The reconstruction of large cranial bone defects by bioactive materials without exogenous cells or growth factors remains a substantial clinical challenge. Here, synthetic fibrous glycopeptide hydrogel (GR gel ) self-assembled by β-sheet RADA16-grafted glucomannan was designed to mimic the glycoprotein composition and the fibrillar architecture of natural extracellular matrix (ECM), which was non-covalently composited with 3D-printed polycaprolactone/nano hydroxyapatite (PCL/nHA) scaffold for cranial bone regeneration . The glycopeptide hydrogel significantly promoted the proliferation, osteogenic differentiation of bone mesenchymal stem cells (BMSCs), which was further augmented by GR gel -induced macrophage M2-phonotype polarization and the effective M2 macrophage-BMSC crosstalk . The repair of critical-size skull bone defect in rat indicated a superior efficacy of PCL/ [email protected] gel implant on bone regeneration and osseointegration , with an average bone area of 83.3% throughout the defect location at 12 weeks post treatment. Furthermore, the osteo-immunomodulatory GR gel induced a reparative microenvironment similar with that in normal cranium, as characterized by an increased percentage of anti-inflammatory M2 macrophages and osteoblasts, and high-level vascularization . Collectively, the composite scaffold developed here with macrophage polarization-mediated osteo-immunomodulation may represent a promising implant for expediting in situ bone regeneration by providing biochemical and osteoinductive cues at the injured tissue.

Rediscovering peritoneal macrophages in a murine endometriosis model

Yuan Ming,Li Dong,An Min,Li Qiuju,Zhang Lu,Wang Guoyun

STUDY QUESTIONWhat are the features of peritoneal macrophage subgroups and T helper cells in the development of murine endometriosis?SUMMARY ANSWERDuring the development of endometriosis in a murine model, large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs) are polarized into M1 and M2 cells, respectively, and the proportions of T helper (Th) 1, Th17 and T regulatory (Treg) cells are increased.WHAT IS KNOWN ALREADYNumerous studies investigating the etiology and pathogenesis of endometriosis have focused on the polarization states of peritoneal macrophages in endometriosis models and patients, but the results are inconclusive. Further studies indicate that peritoneal macrophages are composed of two distinct subsets: LPMs and SPMs, although their roles in endometriosis are unknown.STUDY DESIGN, SIZE, DURATIONThis study involves a prospective and randomized experiment. Fifty C57BL/6 female mice were randomly allocated to five control and five experimental groups (n = 5/group) according to the presence or absence of transplantation. The transplant periods are 0.25, 3, 14, 28 and 42 days.PARTICIPANTS/MATERIALS, SETTING, METHODSC57BL/6 mice were utilized to establish an endometriosis model by i.p. injection of allogeneic endometrial segments. Dynamic changes of peritoneal macrophage subsets and polarization profiles were evaluated by flow cytometry (FCM). Macrophage morphology and density were assessed by cell counting under a microscope. Dynamic changes of Th1, Th2, Th17 and Treg cells were estimated by FCM.MAIN RESULTS AND THE ROLE OF CHANCEPeritoneal macrophages are composed of two distinct subsets: LPMs and SPMs. The proportion of SPMs increased immediately after peritoneal injection of endometrial tissues, whereas LPMs showed an opposite trend. Peritoneal macrophages differentiated into both M1 and M2 macrophages. The bidirectional polarization of macrophages was caused by the inverse trends of polarization of LPMs and SPMs. Consistently, the proportions of Th1, Th17 and Treg cells were all increased in mice with endometriosis.LARGE SCALE DATAN/A.LIMITATIONS, REASONS FOR CAUTIONIn this study, detection was only performed in a murine endometriosis model. Clinical data and more intervention experiments are required in understanding the roles of LPMs and SPMs in endometriosis.WIDER IMPLICATIONS OF THE FINDINGSThe dramatic changes of LPMs and SPMs in proportion and polarization profiles clarified the varying differentiation states of peritoneal macrophages. In addition, LPMs and SPMs may play different roles in the pathogenesis of endometriosis in different stages of endometriosis. Therefore, the new classification should be included in future relevant basic and clinical studies on endometriosis.STUDY FUNDING/COMPETING INTEREST(S)This research was supported totally by grant 81270671 from the National Natural Science Foundation of China. The authors report no conflict of interest.

Chiral hydrogels facilitate rapid diabetic wound healing by promoting macrophage M2 polarization and cellular proliferation

Yi-Ping Hu,Kui Xiao,Ma-Chao Si,Cai-Xia Wang,Yong Miao,Zhi-Qi Hu

Macrophage M2 polarization is one of the most important processes for promoting diabetic wound healing, but how chirality regulates this process is still unknown. Thus, chiral hydrogels based on amino acid derivatives (L-Fmoc-NV and D-Fmoc-NV) were applied to investigate the influence of chirality on macrophage M2 polarization. Compared to the right-handed nanofibers of D-Fmoc-NV, the left-handed helical nanofibers of L-Fmoc-NV can significantly affect the polarization of macrophages towards the M2 phenotype. Furthermore, the left-handed helical nanofibers of L-Fmoc-NV can more significantly promote cell adhesion, proliferation, and antibacterial responses than the nanofibers of D-Fmoc-NV. Based on these advantages of the left-handed helical nanofibers of L-Fmoc-NV, a more expedited healing trajectory (∼14 days) was observed in the L-Fmoc-NV systems. This work offers a new approach for chronic diabetic wound healing via the chirality-induced polarization of macrophages towards the M2 phenotype.

Melatonin and calcium phosphate crystal-loaded poly(L-lactic acid) porous microspheres reprogram macrophages to improve bone repair

Yiyang Huang,Yichang Xu,Ziyan Huang,Jiannan Mao,Yujian Hui,Min Rui,Xinzhao Jiang,Jie Wu,Zhouye Ding,Yu Feng,Yong Gu,Liang Chen

The bone immune microenvironment can influence the occurrence and progression of bone defects. To date, research on promoting macrophage M2 polarization to improve bone injury repair has been insufficient. In this study, we designed an injectable poly(L-lactic acid) (PLLA) porous microsphere that forms calcium phosphate crystals on its surface by binding to melatonin, followed by bionanomimetic mineralization in vitro. The microsphere is injectable and degradable, and its release of melatonin (MT) and calcium phosphate (CaP) crystals promotes macrophage M2 polarization, reprogramming of macrophages, and enhanced osteogenesis. After LPS stimulation, the proportion of M2-polarized macrophages in the MS@CaP@MT group was 39.2 ± 2.7%, significantly higher than that in other groups (P < 0.05). Further, in the MS@CaP@MT group, rats exhibited bone mineral densities of 129.4 ± 12.8 mg cc−1 at 2 weeks and 171.6 ± 13.6 mg cc−1 at 4 weeks in the defect area, which were significantly higher than those in other groups (P < 0.05). Using an animal model of femoral condylar defects, we demonstrated that MT PLLA porous microspheres loaded with calcium phosphate crystals can improve the immune microenvironment and form a microsphere-centered osteogenesis model. This significantly accelerates bone defect repair and provides a potential strategy for bone defect treatment.

FHL2 regulates microglia M1/M2 polarization after spinal cord injury via PARP14-depended STAT1/6 pathway

Aihua Xu,Yang Yang,Yang Shao,Manyu Jiang,Yongxin Sun,Bo Feng

Neuronal apoptosis and inflammation exacerbate the secondary injury after spinal cord injury (SCI). Four and a half domains 2 (FHL2) is a multifunctional scaffold protein with tissue- and cell-type specific effects on the regulation of inflammation, but its role in SCI remains unclear. The T10 mouse spinal cord contusion model was established, and the mice were immediately injected with lentiviruses carrying FHL2 shRNA after SCI. The results showed that FHL2 expression was increased following SCI, and then gradually decreased. Moreover, FHL2 depletion aggravated functional impairment, neuronal necrosis, and enlarged lesion cavity areas in the injured spinal cord. FHL2 deficiency facilitated neuronal apoptosis by elevating cleaved caspase 3/9 expression, neuroinflammation by regulating microglia polarization, and bone loss. Indeed, FHL2 deficiency increased the secretion of TNF-α and IL-6, M1 microglia polarization, and the activation of STAT1 pathway but decreased the secretion of IL-10 and IL-4, M2 microglia polarization, and the activation of the STAT6 pathway in the spinal cord. In vitro , FHL2 silencing promoted LPS + IFN-γ-induced microglia M1 polarization through activating the STAT1 pathway and alleviated IL-4-induced microglia M2 polarization via inhibiting the STAT6 pathway. FHL2 positively regulated the expression of poly (ADP-ribose) polymerase family member 14 (PARP14) by promoting its transcription. PARP14 overexpression inhibited FHL2 silencing-induced microglia M1 polarization and relieved the inhibitory effect of FHL2 silencing on microglia M2 polarization. Collectively, the study suggests that FHL2 reduces the microglia M1/M2 polarization-mediated inflammation via PARP14-dependent STAT1/6 pathway and thereby improves functional recovery after SCI.