The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages ...The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction(q RT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium(CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection(ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB(NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases(MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages,promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.展开更多
Biomaterials as bone substitutes are always considered as foreign bodies that can trigger host immune responses.Traditional designing principles have been always aimed at minimizing the immune reactions by fabricating...Biomaterials as bone substitutes are always considered as foreign bodies that can trigger host immune responses.Traditional designing principles have been always aimed at minimizing the immune reactions by fabricating inert biomaterials.However,clinical evidence revealed that those methods still have limitations and many of which were only feasible in the laboratory.Currently,osteoimmunology,the very pioneering concept is drawing more and more attention-it does not simply regard the immune response as an obstacle during bone healing but emphasizes the intimate relationship of the immune and skeletal system,which includes diverse cells,cytokines,and signaling pathways.Properties of biomaterials like topography,wettability,surface charge,the release of cytokines,mediators,ions and other bioactive molecules can impose effects on immune responses to interfere with the skeletal system.Based on the bone formation mechanisms,the designing methods of the biomaterials change from immune evasive to immune reprogramming.Here,we discuss the osteoimmunomodulatory effects of the new modification strategies—adjusting properties of bone biomaterials to induce a favorable osteoimmune environment.Such strategies showed potential to benefit the development of bone materials and lay a solid foundation for the future clinical application.展开更多
Multiple sclerosis （MS） is an autoimmune demyelinating disease of the central nervous system, and microglia and macrophages play important roles in its pathogenesis. The activation of microglia and macrophages ac- c...Multiple sclerosis （MS） is an autoimmune demyelinating disease of the central nervous system, and microglia and macrophages play important roles in its pathogenesis. The activation of microglia and macrophages ac- companies disease development, whereas depletion of these cells significantly decreases disease severity. Microglia and macrophages usually have diverse and plastic phenotypes. Both pro-inflammatory and anti- inflammatory microglia and macrophages exist in MS and its animal model, experimental autoimmune enceph- alomyelitis. The polarization of microglia and macrophages may underlie the differing functional properties that have been reported. In this review, we discuss the responses and polarization of microglia and macrophages in MS, and their effects on its pathogenesis and repair. Harnessing their beneficial effects by modulating their polarization states holds great promise for the treatment of inflammatory demyelinating diseases.展开更多
Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue.The exact molecular mechanisms controlling this process are still elusive.Here...Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue.The exact molecular mechanisms controlling this process are still elusive.Here,we report that ubiquitin-specific protease 19(USP19)acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization.USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.In addition,USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains.USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4,thereby preventing its p62-mediated selective autophagic degradation.Consistent with these observations,compared to wild-type mice,Usp19−/−mice had decreased M2-like macrophage polarization and increased interleukin-1βsecretion,in response to alum and chitin injections.Thus,we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function,and suggest that USP19 is a potential therapeutic target for inflammatory interventions.展开更多
The role of macrophages （MФ） as the first line of host defense is well accepted. These cells play a central role in orchestrating crucial functions during schistosomal infection. Thus, understanding the functional ...The role of macrophages （MФ） as the first line of host defense is well accepted. These cells play a central role in orchestrating crucial functions during schistosomal infection. Thus, understanding the functional diversity of these cells in the process of infection as well as the mechanisms underlying these events is crucial for developing disease control strategies. In this study, we adopted a Mqb polarization recognition system. M1 macrophage was characterized by expressing CD16/32, IL-12 and iNOS. M2 macrophage was characterized by expressing CD206, IL-10 and arg-1. In vivo （mouse peritoneal macrophages of different infection stages were obtained） and in vitro （different S. japonicum antigens were used to stimulate RAW264.7） were characterized by using the above mentioned system. NCA and ACA stimulated RAW264.7 express significantly higher levels of IL-12 while significantly higher levels of IL-10 were detected after soluble egg antigen （SEA） stimulation. The results showed that dramatic changes of antigen in the microenvironment before and after egg production led to macrophage polarization. Furthermore, through TLR blocking experiments, the TLR4 signaling pathway was found to play a role in the process of macrophage polarization toward M1. Our data suggest that macrophage polarization during S. japonicum infection had significant effects on host immune responses to S. japonicum.展开更多
There have been many chapters written about macrophage polarization.These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape t...There have been many chapters written about macrophage polarization.These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape these polarizing responses.This bias toward immunity is understandable,given the importance of macrophages to host defense.However,macrophages are ubiquitous and are involved in many different cellular processes,and describing them as immune cells is undoubtedly an oversimplification.It disregards their important roles in development,tissue remodeling,wound healing,angiogenesis,and metabolism,to name just a few processes.In this chapter,we propose that macrophages function as transducers in the body.According to Wikipedia,WA transducer is a device that converts energy from one form to another.^The word transducer is a term used to describe both the"sensor,which can interpret a wide range of energy forms,and the"actuator,which can switch voltages or currents to affect the environment.Macrophages are able to sense a seemingly endless variety of inputs from their environment and transduce these inputs into a variety of different response outcomes.Thus,rather than functioning as immune cells,they should be considered more broadly as cellular transducers that interpret microenvironmental changes and actuate vital tissue responses.In this chapter,we will describe some of the sensory stimuli that macrophages perceive and the responses they make to these stimuli to achieve their prime directive,which is the maintenance of homeostasis.展开更多
AIM To investigate the role of peritoneal macrophage(PM) polarization in the therapeutic effect of abdominal paracentesis drainage(APD) on severe acute pancreatitis(SAP).METHODS SAP was induced by 5% Na-taurocholate r...AIM To investigate the role of peritoneal macrophage(PM) polarization in the therapeutic effect of abdominal paracentesis drainage(APD) on severe acute pancreatitis(SAP).METHODS SAP was induced by 5% Na-taurocholate retrograde injection in Sprague-Dawley rats. APD was performed by inserting a drainage tube with a vacuum ball into the lower right abdomen of the rats immediately after the induction of SAP. To verify the effect of APD on macrophages, PMs were isolated and cultured in an environment, with the peritoneal inflammatory environment simulated by the addition of peritoneal lavage in complete RPMI 1640 medium. Hematoxylin and eosin staining was performed. The levels of pancreatitis biomarkers amylase and lipase as well as the levels of inflammatory mediators in the blood and peritoneal lavage were determined. The polarization phenotypes of the PMs were identified by detecting the marker expression of M1/M2 macrophages via flow cytometry, qPCR and immunohistochemical staining. The protein expression in macrophages that had infiltrated the pancreas was determined by Western blot.RESULTS APD treatment significantly reduced the histopathological scores and levels of amylase, lipase, tumor necrosis factor-α and interleukin(IL)-1β, indicating that APD ameliorates the severity of SAP. Importantly, we found that APD treatment polarized PMs towards the M2 phenotype, as evidenced by the reduced number of M1 macrophages and the reduced levels of proinflammatory mediators, such as IL-1β and L-selectin, as well as the increased number of M2 macrophages and increased levels of anti-inflammatory mediators, such as IL-4 and IL-10. Furthermore, in an in vitro study wherein peritoneal lavage from the APD group was added to the cultured PMs to simulate the peritoneal inflammatory environment, PMs also exhibited a dominant M2 phenotype, resulting in a significantly lower level of inflammation. Finally, APD treatment increased the proportion of M2 macrophages and upregulated the expression of the anti-inflammatory protein Ar展开更多
基金supported by the National Natural Science Foundation of China(No.81672205)National Key R&D Programme(No.2016YFC1102100,China)the Shanghai Science and Technology Development Fund(Nos.18DZ2291200and 18441902700,China)
文摘The objective was to investigate the effect of kinsenoside(Kin) treatments on macrophage polarity and evaluate the resulting protection of chondrocytes to attenuate osteoarthritis(OA) progression.RAW264.7 macrophages were polarized to M1/M2 subtypes then administered with different concentrations of Kin. The polarization transitions were evaluated with quantitative real-time polymerase chain reaction(q RT-PCR), confocal observation and flow cytometry analysis. The mechanism of Kin repolarizing M1 macrophages was evaluated by Western blot. Further, macrophage conditioned medium(CM) and IL-1β were administered to chondrocytes. Micro-CT scanning and histological observations were conducted in vivo on anterior cruciate ligament transection(ACLT) mice with or without Kin treatment. We found that Kin repolarized M1 macrophages to the M2 phenotype. Mechanistically, Kin inhibited the phosphorylation of IκBα, which further reduced the downstream phosphorylation of P65 in nuclear factor-κB(NF-κB) signaling. Moreover, Kin inhibited mitogen-activated protein kinases(MAPK) signaling molecules p-JNK, p-ERK and p-P38. Additionally, Kin attenuated macrophage CM and IL-1β-induced chondrocyte damage. In vivo, Kin reduced the infiltration of M1 macrophages,promoted M2 macrophages in the synovium, inhibited subchondral bone destruction and reduced articular cartilage damage induced by ACLT. All the results indicated that Kin is an effective therapeutic candidate for OA treatment.
基金supported by National Natural Science Foundation of China(81873710)Guangdong Financial Fund for High-Caliber Hospital Construction(174-2018-XMZC-0001-03-0125/C-05)+3 种基金the Fundamental Research Funds for the Central Universities(19ykzd15)Guangzhou Foundation for Science and Technology Planning Project,China(201704030083)Open Fund of Guangdong Provincial Key Laboratory of Oral Diseases,Sun Yat-Sen University(KF2018120102)Sun Yat-sen University Science and Technology Achievements Conversion Project(87000-18843231).
文摘Biomaterials as bone substitutes are always considered as foreign bodies that can trigger host immune responses.Traditional designing principles have been always aimed at minimizing the immune reactions by fabricating inert biomaterials.However,clinical evidence revealed that those methods still have limitations and many of which were only feasible in the laboratory.Currently,osteoimmunology,the very pioneering concept is drawing more and more attention-it does not simply regard the immune response as an obstacle during bone healing but emphasizes the intimate relationship of the immune and skeletal system,which includes diverse cells,cytokines,and signaling pathways.Properties of biomaterials like topography,wettability,surface charge,the release of cytokines,mediators,ions and other bioactive molecules can impose effects on immune responses to interfere with the skeletal system.Based on the bone formation mechanisms,the designing methods of the biomaterials change from immune evasive to immune reprogramming.Here,we discuss the osteoimmunomodulatory effects of the new modification strategies—adjusting properties of bone biomaterials to induce a favorable osteoimmune environment.Such strategies showed potential to benefit the development of bone materials and lay a solid foundation for the future clinical application.
基金supported by the National Basic Research Development Program (2011CB504401)the National Natural Science Foundation of China (31171030, 31130024)+1 种基金the Shanghai Pujiang Project (11PJ1412300)the Shanghai Shuguang Project(07SG43)
文摘Multiple sclerosis （MS） is an autoimmune demyelinating disease of the central nervous system, and microglia and macrophages play important roles in its pathogenesis. The activation of microglia and macrophages ac- companies disease development, whereas depletion of these cells significantly decreases disease severity. Microglia and macrophages usually have diverse and plastic phenotypes. Both pro-inflammatory and anti- inflammatory microglia and macrophages exist in MS and its animal model, experimental autoimmune enceph- alomyelitis. The polarization of microglia and macrophages may underlie the differing functional properties that have been reported. In this review, we discuss the responses and polarization of microglia and macrophages in MS, and their effects on its pathogenesis and repair. Harnessing their beneficial effects by modulating their polarization states holds great promise for the treatment of inflammatory demyelinating diseases.
基金This work was supported by the National Key Research and Development Project(2020YFA0908700)the National Natural Science Foundation of China(31870862 and 31700760).
文摘Macrophage polarization to proinflammatory M1-like or anti-inflammatory M2-like cells is critical to mount a host defense or repair tissue.The exact molecular mechanisms controlling this process are still elusive.Here,we report that ubiquitin-specific protease 19(USP19)acts as an anti-inflammatory switch that inhibits inflammatory responses and promotes M2-like macrophage polarization.USP19 inhibited NLRP3 inflammasome activation by increasing autophagy flux and decreasing the generation of mitochondrial reactive oxygen species.In addition,USP19 inhibited the proteasomal degradation of inflammasome-independent NLRP3 by cleaving its polyubiquitin chains.USP19-stabilized NLRP3 promoted M2-like macrophage polarization by direct association with interferon regulatory factor 4,thereby preventing its p62-mediated selective autophagic degradation.Consistent with these observations,compared to wild-type mice,Usp19−/−mice had decreased M2-like macrophage polarization and increased interleukin-1βsecretion,in response to alum and chitin injections.Thus,we have uncovered an unexpected mechanism by which USP19 switches the proinflammatory function of NLRP3 into an anti-inflammatory function,and suggest that USP19 is a potential therapeutic target for inflammatory interventions.
文摘The role of macrophages （MФ） as the first line of host defense is well accepted. These cells play a central role in orchestrating crucial functions during schistosomal infection. Thus, understanding the functional diversity of these cells in the process of infection as well as the mechanisms underlying these events is crucial for developing disease control strategies. In this study, we adopted a Mqb polarization recognition system. M1 macrophage was characterized by expressing CD16/32, IL-12 and iNOS. M2 macrophage was characterized by expressing CD206, IL-10 and arg-1. In vivo （mouse peritoneal macrophages of different infection stages were obtained） and in vitro （different S. japonicum antigens were used to stimulate RAW264.7） were characterized by using the above mentioned system. NCA and ACA stimulated RAW264.7 express significantly higher levels of IL-12 while significantly higher levels of IL-10 were detected after soluble egg antigen （SEA） stimulation. The results showed that dramatic changes of antigen in the microenvironment before and after egg production led to macrophage polarization. Furthermore, through TLR blocking experiments, the TLR4 signaling pathway was found to play a role in the process of macrophage polarization toward M1. Our data suggest that macrophage polarization during S. japonicum infection had significant effects on host immune responses to S. japonicum.
文摘There have been many chapters written about macrophage polarization.These chapters generally focus on the role of macrophages in orchestrating immune responses by highlighting the T-cell-derived cytokines that shape these polarizing responses.This bias toward immunity is understandable,given the importance of macrophages to host defense.However,macrophages are ubiquitous and are involved in many different cellular processes,and describing them as immune cells is undoubtedly an oversimplification.It disregards their important roles in development,tissue remodeling,wound healing,angiogenesis,and metabolism,to name just a few processes.In this chapter,we propose that macrophages function as transducers in the body.According to Wikipedia,WA transducer is a device that converts energy from one form to another.^The word transducer is a term used to describe both the"sensor,which can interpret a wide range of energy forms,and the"actuator,which can switch voltages or currents to affect the environment.Macrophages are able to sense a seemingly endless variety of inputs from their environment and transduce these inputs into a variety of different response outcomes.Thus,rather than functioning as immune cells,they should be considered more broadly as cellular transducers that interpret microenvironmental changes and actuate vital tissue responses.In this chapter,we will describe some of the sensory stimuli that macrophages perceive and the responses they make to these stimuli to achieve their prime directive,which is the maintenance of homeostasis.
基金the National Natural Science Foundation of China,No.81772001,No.8177071311 and No.81502696the National Clinical Key Subject of China,No.41792113+1 种基金the Technology Plan Program of Sichuan Province,No.2015SZ0229,No.2018JY0041 and No.18YYJC0442the Science and Technology Development Plan of Sichuan Province,No.2016YJ0023
文摘AIM To investigate the role of peritoneal macrophage(PM) polarization in the therapeutic effect of abdominal paracentesis drainage(APD) on severe acute pancreatitis(SAP).METHODS SAP was induced by 5% Na-taurocholate retrograde injection in Sprague-Dawley rats. APD was performed by inserting a drainage tube with a vacuum ball into the lower right abdomen of the rats immediately after the induction of SAP. To verify the effect of APD on macrophages, PMs were isolated and cultured in an environment, with the peritoneal inflammatory environment simulated by the addition of peritoneal lavage in complete RPMI 1640 medium. Hematoxylin and eosin staining was performed. The levels of pancreatitis biomarkers amylase and lipase as well as the levels of inflammatory mediators in the blood and peritoneal lavage were determined. The polarization phenotypes of the PMs were identified by detecting the marker expression of M1/M2 macrophages via flow cytometry, qPCR and immunohistochemical staining. The protein expression in macrophages that had infiltrated the pancreas was determined by Western blot.RESULTS APD treatment significantly reduced the histopathological scores and levels of amylase, lipase, tumor necrosis factor-α and interleukin(IL)-1β, indicating that APD ameliorates the severity of SAP. Importantly, we found that APD treatment polarized PMs towards the M2 phenotype, as evidenced by the reduced number of M1 macrophages and the reduced levels of proinflammatory mediators, such as IL-1β and L-selectin, as well as the increased number of M2 macrophages and increased levels of anti-inflammatory mediators, such as IL-4 and IL-10. Furthermore, in an in vitro study wherein peritoneal lavage from the APD group was added to the cultured PMs to simulate the peritoneal inflammatory environment, PMs also exhibited a dominant M2 phenotype, resulting in a significantly lower level of inflammation. Finally, APD treatment increased the proportion of M2 macrophages and upregulated the expression of the anti-inflammatory protein Ar
