Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indi...Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.展开更多
目的分析单核细胞人类白细胞抗原-DR(monocyte human leukocyte antigen-DR,mHLA-DR)表达率的变化在严重创伤继发感染患者的发生、发展以及转归的临床意义。方法选取2019年1月—2022年12月江苏大学附属武进医院收治的88例严重创伤患者...目的分析单核细胞人类白细胞抗原-DR(monocyte human leukocyte antigen-DR,mHLA-DR)表达率的变化在严重创伤继发感染患者的发生、发展以及转归的临床意义。方法选取2019年1月—2022年12月江苏大学附属武进医院收治的88例严重创伤患者作为研究对象,根据观察期内感染情况分为全身感染组33例、局部感染组30例和非感染组25例3组,采用流式细胞术检测患者第1、3、5、7天外周血mHLA-DR表达率。结果全身感染组第7天mHLA-DR表达率(32.79±13.24)%低于第1天(51.41±15.65)%,差异有统计学意义(P<0.05);局部感染组第7天与第1天比较,差异无统计学意义(P>0.05);非感染组第7天mHLA-DR表达率(69.35±9.42)%高于第1天(58.07±11.25)%,差异有统计学意义(P<0.05)。创伤患者mHLA-DR表达率在第5和7天各感染组间比较,差异有统计学意义(P<0.05)。全身感染死亡组第7天与第1、3天mHLA-DR表达率差值分别为(24.61±8.14)%和(12.70±6.24)%,高于生存组,差异有统计学意义(P<0.05)。结论连续动态监测严重创伤感染患者mHLA-DR的表达变化,可能对了解患者病情变化、评估免疫状态以及预后有临床价值。展开更多
By def inition, sepsis refers to a life threatening organ dysfunction due to a dysregulated host response to an infection[1]. More precisely, sepsis triggers a multifaceted response characterized by a simultaneous man...By def inition, sepsis refers to a life threatening organ dysfunction due to a dysregulated host response to an infection[1]. More precisely, sepsis triggers a multifaceted response characterized by a simultaneous manifestation of proinflammatory and anti-inflammatory elements that disrupt mechanisms intended to maintain homeostasis. Initially, an overwhelming hyperinflammatory reaction ensues, resulting in tissue damage and organ dysfunction.展开更多
基金supported by the Key Project of National Natural Science Foundation of China(82130062,82241062 and 81930057)the National Key Research and Development Program of China(2022YFA1104604)+1 种基金the Key Project of Military Medical Innovation Program of Chinese PLA(18CXZ026 and BLJ18J006)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-076)。
文摘Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.
文摘目的分析单核细胞人类白细胞抗原-DR(monocyte human leukocyte antigen-DR,mHLA-DR)表达率的变化在严重创伤继发感染患者的发生、发展以及转归的临床意义。方法选取2019年1月—2022年12月江苏大学附属武进医院收治的88例严重创伤患者作为研究对象,根据观察期内感染情况分为全身感染组33例、局部感染组30例和非感染组25例3组,采用流式细胞术检测患者第1、3、5、7天外周血mHLA-DR表达率。结果全身感染组第7天mHLA-DR表达率(32.79±13.24)%低于第1天(51.41±15.65)%,差异有统计学意义(P<0.05);局部感染组第7天与第1天比较,差异无统计学意义(P>0.05);非感染组第7天mHLA-DR表达率(69.35±9.42)%高于第1天(58.07±11.25)%,差异有统计学意义(P<0.05)。创伤患者mHLA-DR表达率在第5和7天各感染组间比较,差异有统计学意义(P<0.05)。全身感染死亡组第7天与第1、3天mHLA-DR表达率差值分别为(24.61±8.14)%和(12.70±6.24)%,高于生存组,差异有统计学意义(P<0.05)。结论连续动态监测严重创伤感染患者mHLA-DR的表达变化,可能对了解患者病情变化、评估免疫状态以及预后有临床价值。
文摘By def inition, sepsis refers to a life threatening organ dysfunction due to a dysregulated host response to an infection[1]. More precisely, sepsis triggers a multifaceted response characterized by a simultaneous manifestation of proinflammatory and anti-inflammatory elements that disrupt mechanisms intended to maintain homeostasis. Initially, an overwhelming hyperinflammatory reaction ensues, resulting in tissue damage and organ dysfunction.
