儿童肥胖相关哮喘CD4+T细胞与气道平滑肌的相互作用
2022/10/17
摘要
论据：儿童肥胖相关哮喘是一种非特应性哮喘表型，其疾病负担高，有效治疗手段少。外周血TH细胞中RhoGTPase上调与表型相关，但这种关联的机制尚不清楚。
目的：探讨TH细胞中RhoGTPase CDC42上调与气道平滑肌（ASM）生物学相关的机制。
方法：研究肥胖哮喘和健康体重哮喘TH细胞的趋化性及其与肥胖和健康体重非哮喘ASM的粘附性。转录组学和蛋白质组学用于明确肥胖和健康体重哮喘TH细胞粘附对肥胖或健康体重ASM生物学的差异影响。
检测和主要结果：CDC42上调时的肥胖性哮喘TH细胞趋化性强而CDC42抑制时减弱。与健康体重哮喘TH细胞与健康体重ASM相比，肥胖哮喘TH淋巴细胞与肥胖ASM的粘附性更强。与健康体重ASM的共培养相比，肥胖哮喘TH细胞与肥胖ASM共培养在肌动蛋白细胞骨架组织、跨膜受体蛋白激酶信号传导和细胞有丝分裂相关基因和蛋白表达合成方面上调，而在细胞外基质组织合成方面下调。靶向基因评估显示TH细胞基因中IFNG、TNF和CD247上调，平滑肌基因中AKT、RHOA和CD38上调，PKCA下调。
结论：肥胖性哮喘TH细胞具有不受抑制的趋化性，并且更粘附于肥胖性ASM，这与平滑肌增殖相关基因和蛋白的上调以及非特应性TH细胞的相互激活有关。
Crosstalk Between CD4+ T Cells and Airway Smooth Muscle in Pediatric Obesity-related Asthma
Changsuek Yon, David A Thompson, Joseph A Jude, Reynold A Panettieri Jr, Deepa Rastogi
Abstract
Rationale: Pediatric obesity-related asthma is a non-atopic asthma phenotype with high disease burden and few effective therapies. RhoGTPase upregulation in peripheral blood TH cells is associated with the phenotype but the mechanisms that underlie this association are not known.
Objective: To investigate the mechanisms by which upregulation of CDC42, a RhoGTPase, in TH cells, is associated with airway smooth muscle (ASM) biology.
Methods: Chemotaxis of obese asthma and healthy-weight asthma TH cells, and their adhesion to obese and healthy-weight non-asthmatic ASM, was investigated. Transcriptomics and proteomics were used to determine the differential effect of obese and healthy-weight asthma TH cell adhesion to obese or healthy-weight ASM biology.
Measurement and main results: Chemotaxis of obese asthma TH cells with CDC42 upregulation was resistant to CDC42 inhibition. Obese asthma TH cells were more adherent to obese ASM as compared to healthy-weight asthma TH cells to healthy-weight ASM. Compared to co-culture with healthy-weight ASM, obese asthma TH cell co-culture with obese ASM was positively enriched for genes and proteins involved in actin cytoskeleton organization, transmembrane receptor protein kinase signaling, and cell mitosis, and negatively enriched for extracellular matrix organization. Targeted gene evaluation revealed upregulation of IFNG, TNF and CD247 among TH cell genes, and of AKT, RHOA and CD38, with downregulation of PKCA, among smooth muscle genes.
Conclusions: Obese asthma TH cells have uninhibited chemotaxis and are more adherent to obese ASM, which is associated with upregulation of genes and proteins associated with smooth muscle proliferation and reciprocal non-atopic TH cell activation.
论据：儿童肥胖相关哮喘是一种非特应性哮喘表型，其疾病负担高，有效治疗手段少。外周血TH细胞中RhoGTPase上调与表型相关，但这种关联的机制尚不清楚。
目的：探讨TH细胞中RhoGTPase CDC42上调与气道平滑肌（ASM）生物学相关的机制。
方法：研究肥胖哮喘和健康体重哮喘TH细胞的趋化性及其与肥胖和健康体重非哮喘ASM的粘附性。转录组学和蛋白质组学用于明确肥胖和健康体重哮喘TH细胞粘附对肥胖或健康体重ASM生物学的差异影响。
检测和主要结果：CDC42上调时的肥胖性哮喘TH细胞趋化性强而CDC42抑制时减弱。与健康体重哮喘TH细胞与健康体重ASM相比，肥胖哮喘TH淋巴细胞与肥胖ASM的粘附性更强。与健康体重ASM的共培养相比，肥胖哮喘TH细胞与肥胖ASM共培养在肌动蛋白细胞骨架组织、跨膜受体蛋白激酶信号传导和细胞有丝分裂相关基因和蛋白表达合成方面上调，而在细胞外基质组织合成方面下调。靶向基因评估显示TH细胞基因中IFNG、TNF和CD247上调，平滑肌基因中AKT、RHOA和CD38上调，PKCA下调。
结论：肥胖性哮喘TH细胞具有不受抑制的趋化性，并且更粘附于肥胖性ASM，这与平滑肌增殖相关基因和蛋白的上调以及非特应性TH细胞的相互激活有关。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Am J Respir Crit Care Med. 2022 Oct 4. doi: 10.1164/rccm.202205-0985OC.)
(Am J Respir Crit Care Med. 2022 Oct 4. doi: 10.1164/rccm.202205-0985OC.)
Crosstalk Between CD4+ T Cells and Airway Smooth Muscle in Pediatric Obesity-related Asthma
Changsuek Yon, David A Thompson, Joseph A Jude, Reynold A Panettieri Jr, Deepa Rastogi
Abstract
Rationale: Pediatric obesity-related asthma is a non-atopic asthma phenotype with high disease burden and few effective therapies. RhoGTPase upregulation in peripheral blood TH cells is associated with the phenotype but the mechanisms that underlie this association are not known.
Objective: To investigate the mechanisms by which upregulation of CDC42, a RhoGTPase, in TH cells, is associated with airway smooth muscle (ASM) biology.
Methods: Chemotaxis of obese asthma and healthy-weight asthma TH cells, and their adhesion to obese and healthy-weight non-asthmatic ASM, was investigated. Transcriptomics and proteomics were used to determine the differential effect of obese and healthy-weight asthma TH cell adhesion to obese or healthy-weight ASM biology.
Measurement and main results: Chemotaxis of obese asthma TH cells with CDC42 upregulation was resistant to CDC42 inhibition. Obese asthma TH cells were more adherent to obese ASM as compared to healthy-weight asthma TH cells to healthy-weight ASM. Compared to co-culture with healthy-weight ASM, obese asthma TH cell co-culture with obese ASM was positively enriched for genes and proteins involved in actin cytoskeleton organization, transmembrane receptor protein kinase signaling, and cell mitosis, and negatively enriched for extracellular matrix organization. Targeted gene evaluation revealed upregulation of IFNG, TNF and CD247 among TH cell genes, and of AKT, RHOA and CD38, with downregulation of PKCA, among smooth muscle genes.
Conclusions: Obese asthma TH cells have uninhibited chemotaxis and are more adherent to obese ASM, which is associated with upregulation of genes and proteins associated with smooth muscle proliferation and reciprocal non-atopic TH cell activation.
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