Neutrophil extracellular trap-induced intermediate monocytes trigger macrophage activation syndrome in adult-onset Still’s disease

• Published in: BMC medicine Vol. 21; no. 1; pp. 507 - 15
• Main Authors: Jia, Jinchao, Wang, Mengyan, Ma, Yuning, Meng, Jianfen, Zhu, Dehao, Chen, Xia, Shi, Hui, Sun, Yue, Liu, Honglei, Cheng, Xiaobing, Su, Yutong, Ye, Junna, Chi, Huihui, Liu, Tingting, Zhou, Zhuochao, Wang, Fan, Chen, Longfang, Yi, Da, Xiao, Yu, Yang, Chengde, Teng, Jialin, Hu, Qiongyi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 20.12.2023; BioMed Central; BMC
• Subjects: Adult-onset Still’s disease; Analysis; Antibodies; Arthritis; Biomarkers; CD16 antigen; CD163 antigen; CD80 antigen; CD86 antigen; Cell activation; Chemokines; Coronaviruses; COVID-19; CXCL10; CXCL10 protein; Cytokine storm; Cytokines; Deoxyribonuclease; Deoxyribonucleic acid; Disease; DNA; DNA sensing; Enzyme-linked immunosorbent assay; Fever; Flow cytometry; Gene expression; Gene sequencing; Health aspects; Immune system; Inflammasomes; Inflammation; Inflammatory diseases; Innate immunity; Leukocytes (neutrophilic); Lymphocytes; Macrophages; Measurement; Monocyte subset; Monocytes; mRNA; Neutrophil extracellular traps; Neutrophils; Pathogenesis; Phagocytes; Phagocytosis; Regulatory mechanisms (biology); Ribonucleic acid; RNA; RNA sequencing; Therapeutic targets; Tumor necrosis factor-TNF; China; United States > US; Japan; CXCL10; Monocyte subset; Adult-onset Still’s disease; DNA sensing; Neutrophil extracellular traps
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-023-03231-9

Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disease characterized by innate immune system activation, with a high risk for macrophage activation syndrome (MAS). MAS development is associated with monocyte/macrophage activation and cytokine storm. Monocytes consist of three different subsets, classical monocytes (CMs, CD14 CD16 -), intermediate monocytes (IMs, CD14 CD16 +), and non-classical monocytes (NCMs, CD14 CD16 +), each has distinct roles in inflammatory regulation. However, the frequencies and regulatory mechanism of monocyte subsets in AOSD patients have not been identified. We performed flow cytometry, RNA sequencing, phagocytosis analysis, and enzyme-linked immunosorbent assay to evaluate monocyte subsets, cell functions, and potential biomarkers. The effect of neutrophil extracellular traps (NETs) on monocytes was determined by evaluating mRNA levels of DNA sensors, surface CD16 expression, and inflammasome pathway activation. Higher proportions of intermediate monocytes (IMs) were identified in active AOSD patients. IMs displayed higher expression of CD80, CD86, HLA-DR, and CD163 than CMs and NCMs. CD163 upregulation was noted on AOSD IMs, accompanied by increased phagocytic activity and elevated cytokine/chemokine production, including IL-1β, IL-6, CCL8, and CXCL10. The frequencies of IMs were correlated with disease activity and higher in AOSD patients with MAS (AOSD-MAS). CCL8 and CXCL10 were highly expressed in RNA sequencing of monocytes from AOSD-MAS patients and plasma CXCL10 level could serve as a potential biomarker for AOSD-MAS. Moreover, DNA-sensing pathway was activated in monocytes from AOSD-MAS patients. Stimulation with NETs derived from AOSD induced DNA sensor expression, the expansion of IMs, and inflammasome pathway activation. These effects can be abrogated by DNase I treatment. Our results demonstrated that the proportions of IMs were elevated in AOSD and associated with MAS. The DNA component in NETs from AOSD plays an important role in the formation of IMs, shedding new light for the therapeutic target.