Autoimmune-related skin diseases are a group of disorders with diverse etiology and pathophysiology involved in autoimmunity.Genetics and environmental factors may contribute to the development of these autoimmune dis...Autoimmune-related skin diseases are a group of disorders with diverse etiology and pathophysiology involved in autoimmunity.Genetics and environmental factors may contribute to the development of these autoimmune disorders.Although the etiology and pathogenesis of these disorders are poorly understood,environmental variables that induce aberrant epigenetic regulations may provide some insights.Epigenetics is the study of heritable mechanisms that regulate gene expression without changing DNA sequences.The most important epigenetic mechanisms are DNA methylation,histone modification,and noncoding RNAs.In this review,we discuss the most recent findings regarding the function of epigenetic mechanisms in autoimmune-related skin disorders,including systemic lupus erythematosus,bullous skin diseases,psoriasis,and systemic sclerosis.These findings will expand our understanding and highlight the possible clinical applications of precision epigenetics approaches.展开更多
Objective:Interleukin-1β(IL-1β)and high-mobility group box 1(HMGB1)are widely known damage-associated molecular patterns(DAMPs).However,their expression and secretion in different skin diseases,especially in inflamm...Objective:Interleukin-1β(IL-1β)and high-mobility group box 1(HMGB1)are widely known damage-associated molecular patterns(DAMPs).However,their expression and secretion in different skin diseases,especially in inflammatory skin disorders,remain to be further elucidated.This study was performed to explore and compare the transcriptional and secretory levels of IL-1β and HMGB1 in keratinocytes under 3 types of stimulation:ultraviolet B(UVB)irradiation;co-stimulation by tumor necrosis factor-α(TNF-α)and interferon-γ(IFN-γ)(simulation of T helper 1 cell inflammatory challenge);and psoriasis-like stimulation by M5,a mixture of 5 proinflammatory cytokines.Methods:We used quantitative reverse-transcription polymerase chain reaction to determine the transcription levels of IL-1β and HMGB1.Western blotting and enzyme-linked immunosorbent assay were used to detect the secretion levels of IL-1β and HMGB1.The results were statistically analyzed by t test.Results:A rapid transcriptional and secretory response of IL-1β from keratinocytes occurred in all 3 types of stimulation mimicking common inflammatory environments(P<0.05).Transcription of HMGB1 was inhibited in all 3 types of stimulation(P<0.05),but secretion was increased after exposure to UVB irradiation and co-stimulation by TNF-α and IFN-γ(P<0.05).We observed no change in the secretion level of HMGB1 after treatment with M5(P=0.196).Conclusion:IL-1β is a critical cytokine for the immunomodulatory functions of keratinocytes in inflammatory responses.In this study,keratinocytes restrained transcription of HMGB1 when the secretion of HMGB1 was induced in certain stimulations(eg,by UVB exposure or stimulation by TNF-α and IFN-γ).展开更多
Objective:The interrelationship between apoptosis and autophagy plays an important role in many pathophysiological processes,however,whether their interplay is involved in allergic contact dermatitis(ACD)has not yet b...Objective:The interrelationship between apoptosis and autophagy plays an important role in many pathophysiological processes,however,whether their interplay is involved in allergic contact dermatitis(ACD)has not yet been elucidated.So,we conducted this study to determine whether keratinocyte-specific autophagy-related gene 5(ATG5)deficiency can regulate apoptosis to inhibit skin damage in mice with 2,4-dinitrochlorobenzene(DNCB)-induced ACD.Methods:This study involved keratinocyte-specificAtg5 conditional knockout(cKO)mice(Krt14cre/+-Atg5flox/flox)and control mice(Krt14+/+-Atg5flox/flox).We painted DNCB on the right ear of each mouse to induce ACD.Dermatitis scoring and measurements of ear weight and thickness were performed to evaluate inflammation levels.An immunohistochemical assay was performed to analyze immune cell infiltration.Histological study and TUNEL staining were performed to compare the differences in skin lesions betweenAtg5 cKO mice and control mice.Immunofluorescence and western blotting were used to examine the levels of ATG5 and apoptosis-related protein.The results were statistically analyzed byt test.Results:After DNCB stimulation of mice ears,we observed a more severe phenotype inAtg5 cKO mice than in control mice(dermatitis score:7.500±2.588vs.3.250±0.822,P=0.003).Further analysis of ATG5 protein confirmed keratinocyte-specific ablation ofAtg5 in cKO mice and showed that DNCB did not influence ATG5 expression.Immunohistochemistry assay revealed that the infiltrated immune cells were not involved in aggravation of the phenotype of DNCB-stimulatedAtg5 cKO mice.However,the histological study(P=0.024),TUNEL staining(P=0.024),immunofluorescence(P=0.036),and western blotting showed that the increase in keratinocyte death,especially apoptosis,contributed to aggravation of the phenotype of DNCB-stimulatedAtg5 cKO mice.Conclusion:Deficiency ofAtg5 in keratinocytes increases apoptosis,aggravating skin damage in DNCB-induced ACD mice.This has no relationship with the involvement of immune cells.展开更多
As a chronic systemic autoimmune disease,systemic lupus erythematosus(SLE)can influence multiple organs and systems.Although the pathological basis and risk factors for SLE have been extensively investigated,the exact...As a chronic systemic autoimmune disease,systemic lupus erythematosus(SLE)can influence multiple organs and systems.Although the pathological basis and risk factors for SLE have been extensively investigated,the exact pathogenesis of SLE remains to be explored.However,there is increasing evidence that T-cell−Bcell interactions promote the development of SLE,resulting in the generation of high-affinity antibodies[1].Tfh cells,a subgroup of T cells,can promote the formation of germinal centers,the maturation of B cells,and the differentiation of plasma cells[2].It has been found that multiple transcription factors(TFs)can regulate the generation of Tfh cells.For instance,B-cell lymphoma-6(BCL-6),an evolutionarily conserved zinc-finger protein,is an important positive transcription factor responsible for the differentiation and maturation of Tfh cells.In addition to maintaining the phenotype and GC response of Tfh cells,BCL-6 can also regulate the dynamics of T-cell−B-cell interactions and improve the efficiency of delivering help to B cells[3].展开更多
Systemic lupus erythematosus(SLE)is a complicated autoimmune disease affecting multiple systems and organs.It is highly heterogeneous,and it preferentially affects women at childbearing age,causing worldwide social bu...Systemic lupus erythematosus(SLE)is a complicated autoimmune disease affecting multiple systems and organs.It is highly heterogeneous,and it preferentially affects women at childbearing age,causing worldwide social burden.The pathogenesis of SLE mostly involves genetic predisposition,epigenetic dysregulation,overactivation of the immune system,and environment factors.Human microbiome,which is mostly composed of microbiota colonized in the gut,skin,and oral cavity,provides a natural microbiome barrier against environmental risks.The past decade of research has demonstrated a strong association between microbiota and metabolic diseases or gastrointestinal diseases.However,the role of microbiota in autoimmunity remains largely unknown until recently,when the technological and methodological progress facilitates further microbiota research in SLE.In this review,the latest research about the role and mechanisms of microbiota in SLE and the advances in the development of diagnostic and therapeutic strategies based on microbiota for SLE were summarized.展开更多
基金CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2021-I2M-1-059)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(No.2020-RC320-003)+1 种基金the National Natural Science Foundation of China(No.81830097)Special Program of National Natural Science Foundation of China(No.32141004).
文摘Autoimmune-related skin diseases are a group of disorders with diverse etiology and pathophysiology involved in autoimmunity.Genetics and environmental factors may contribute to the development of these autoimmune disorders.Although the etiology and pathogenesis of these disorders are poorly understood,environmental variables that induce aberrant epigenetic regulations may provide some insights.Epigenetics is the study of heritable mechanisms that regulate gene expression without changing DNA sequences.The most important epigenetic mechanisms are DNA methylation,histone modification,and noncoding RNAs.In this review,we discuss the most recent findings regarding the function of epigenetic mechanisms in autoimmune-related skin disorders,including systemic lupus erythematosus,bullous skin diseases,psoriasis,and systemic sclerosis.These findings will expand our understanding and highlight the possible clinical applications of precision epigenetics approaches.
基金supported by grants from the National Natural Science Foundation of China(81972952,81872531,82173438,and 82273550)Nanjing Incubation Program for National Clinical Research Center(2019060001)+2 种基金CAMS Innovation Fund for Medical Sciences(2021-1-I2M-059,2017-I2M-1-017)Jiangsu Province Foundation(LGY2018095,WSW-016)PhD Programs Foundation of Ministry of Education of China(No.20131106120046)
文摘Objective:Interleukin-1β(IL-1β)and high-mobility group box 1(HMGB1)are widely known damage-associated molecular patterns(DAMPs).However,their expression and secretion in different skin diseases,especially in inflammatory skin disorders,remain to be further elucidated.This study was performed to explore and compare the transcriptional and secretory levels of IL-1β and HMGB1 in keratinocytes under 3 types of stimulation:ultraviolet B(UVB)irradiation;co-stimulation by tumor necrosis factor-α(TNF-α)and interferon-γ(IFN-γ)(simulation of T helper 1 cell inflammatory challenge);and psoriasis-like stimulation by M5,a mixture of 5 proinflammatory cytokines.Methods:We used quantitative reverse-transcription polymerase chain reaction to determine the transcription levels of IL-1β and HMGB1.Western blotting and enzyme-linked immunosorbent assay were used to detect the secretion levels of IL-1β and HMGB1.The results were statistically analyzed by t test.Results:A rapid transcriptional and secretory response of IL-1β from keratinocytes occurred in all 3 types of stimulation mimicking common inflammatory environments(P<0.05).Transcription of HMGB1 was inhibited in all 3 types of stimulation(P<0.05),but secretion was increased after exposure to UVB irradiation and co-stimulation by TNF-α and IFN-γ(P<0.05).We observed no change in the secretion level of HMGB1 after treatment with M5(P=0.196).Conclusion:IL-1β is a critical cytokine for the immunomodulatory functions of keratinocytes in inflammatory responses.In this study,keratinocytes restrained transcription of HMGB1 when the secretion of HMGB1 was induced in certain stimulations(eg,by UVB exposure or stimulation by TNF-α and IFN-γ).
基金supported by grants from the National Natural Science Foundation of China(Nos.81872531,81972952,82173438,and 82273550)the CAMS Innovation Fund for Medical Sciences(CIFMS)(No.2021-I2M-1-059)+2 种基金the Nanjing Incubation Program for National Clinical Research Center(No.2019060001)Jiangsu Province Foundation(Nos.LGY2018095 and WSW-016)the Ph.D.Programs Foundation of the Ministry of Education of China(No.20131106120046)。
文摘Objective:The interrelationship between apoptosis and autophagy plays an important role in many pathophysiological processes,however,whether their interplay is involved in allergic contact dermatitis(ACD)has not yet been elucidated.So,we conducted this study to determine whether keratinocyte-specific autophagy-related gene 5(ATG5)deficiency can regulate apoptosis to inhibit skin damage in mice with 2,4-dinitrochlorobenzene(DNCB)-induced ACD.Methods:This study involved keratinocyte-specificAtg5 conditional knockout(cKO)mice(Krt14cre/+-Atg5flox/flox)and control mice(Krt14+/+-Atg5flox/flox).We painted DNCB on the right ear of each mouse to induce ACD.Dermatitis scoring and measurements of ear weight and thickness were performed to evaluate inflammation levels.An immunohistochemical assay was performed to analyze immune cell infiltration.Histological study and TUNEL staining were performed to compare the differences in skin lesions betweenAtg5 cKO mice and control mice.Immunofluorescence and western blotting were used to examine the levels of ATG5 and apoptosis-related protein.The results were statistically analyzed byt test.Results:After DNCB stimulation of mice ears,we observed a more severe phenotype inAtg5 cKO mice than in control mice(dermatitis score:7.500±2.588vs.3.250±0.822,P=0.003).Further analysis of ATG5 protein confirmed keratinocyte-specific ablation ofAtg5 in cKO mice and showed that DNCB did not influence ATG5 expression.Immunohistochemistry assay revealed that the infiltrated immune cells were not involved in aggravation of the phenotype of DNCB-stimulatedAtg5 cKO mice.However,the histological study(P=0.024),TUNEL staining(P=0.024),immunofluorescence(P=0.036),and western blotting showed that the increase in keratinocyte death,especially apoptosis,contributed to aggravation of the phenotype of DNCB-stimulatedAtg5 cKO mice.Conclusion:Deficiency ofAtg5 in keratinocytes increases apoptosis,aggravating skin damage in DNCB-induced ACD mice.This has no relationship with the involvement of immune cells.
基金This work was supported by grants from the National Natural Science Foundation of China(Nos.81830097,81972921)the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences(2021-RC320-001,2020-RC320-003)+2 种基金the Hunan Provincial Natural Science Foundation of China(No.2020JJ5849)the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University(No.YX202101)Fundamental Research Funds for the Central Universities of Central South University(No.1053320216463).
文摘As a chronic systemic autoimmune disease,systemic lupus erythematosus(SLE)can influence multiple organs and systems.Although the pathological basis and risk factors for SLE have been extensively investigated,the exact pathogenesis of SLE remains to be explored.However,there is increasing evidence that T-cell−Bcell interactions promote the development of SLE,resulting in the generation of high-affinity antibodies[1].Tfh cells,a subgroup of T cells,can promote the formation of germinal centers,the maturation of B cells,and the differentiation of plasma cells[2].It has been found that multiple transcription factors(TFs)can regulate the generation of Tfh cells.For instance,B-cell lymphoma-6(BCL-6),an evolutionarily conserved zinc-finger protein,is an important positive transcription factor responsible for the differentiation and maturation of Tfh cells.In addition to maintaining the phenotype and GC response of Tfh cells,BCL-6 can also regulate the dynamics of T-cell−B-cell interactions and improve the efficiency of delivering help to B cells[3].
基金This work is supported by CAMS Innovation Fund for Medical Sciences(No.2021-I2M-1-059)the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(Nos.2020-RC320-003 and 2021-RC320-001).
文摘Systemic lupus erythematosus(SLE)is a complicated autoimmune disease affecting multiple systems and organs.It is highly heterogeneous,and it preferentially affects women at childbearing age,causing worldwide social burden.The pathogenesis of SLE mostly involves genetic predisposition,epigenetic dysregulation,overactivation of the immune system,and environment factors.Human microbiome,which is mostly composed of microbiota colonized in the gut,skin,and oral cavity,provides a natural microbiome barrier against environmental risks.The past decade of research has demonstrated a strong association between microbiota and metabolic diseases or gastrointestinal diseases.However,the role of microbiota in autoimmunity remains largely unknown until recently,when the technological and methodological progress facilitates further microbiota research in SLE.In this review,the latest research about the role and mechanisms of microbiota in SLE and the advances in the development of diagnostic and therapeutic strategies based on microbiota for SLE were summarized.