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Genetic landscape and immune mechanism of monocytes associated with the progression of acute-on-chronic liver failure

OBJECTIVE: Acute-on-chronic liver failure (ACLF) has a high prevalence and short-term mortality. Monocytes play an important role in the development of ACLF. However, the monocyte subpopulations with unique features and functions in ACLF and associated with disease progression remain poorly understo...

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Detalles Bibliográficos
Autores principales: Yao, Jia, Liu, Tian, Zhao, Qiang, Ji, Yaqiu, Bai, Jinjia, Wang, Han, Yao, Ruoyu, Zhou, Xiaoshuang, Chen, Yu, Xu, Jun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer India 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10224851/
https://www.ncbi.nlm.nih.gov/pubmed/36626090
http://dx.doi.org/10.1007/s12072-022-10472-y
Descripción
Sumario:OBJECTIVE: Acute-on-chronic liver failure (ACLF) has a high prevalence and short-term mortality. Monocytes play an important role in the development of ACLF. However, the monocyte subpopulations with unique features and functions in ACLF and associated with disease progression remain poorly understood. We investigated the specific monocyte subpopulations associated with ACLF progression and their roles in inflammatory responses using the single-cell RNA sequencing (scRNA-seq). METHODS: We performed scRNA-seq on 17,310 circulating monocytes from healthy controls and ACLF patients and genetically defined their subpopulations to characterize specific monocyte subpopulations associated with ACLF progression. RESULTS: Five monocyte subpopulations were obtained, including pro-inflammatory monocytes, CD16 monocytes, HLA monocytes, megakaryocyte-like monocytes, and NK-like monocytes. Comparisons of the monocytes between ACLF patients and healthy controls showed that the pro-inflammatory monocytes had the most significant gene changes, among which the expressions of genes related to inflammatory responses and cell metabolism were significantly increased while the genes related to cell cycle progression were significantly decreased. Furthermore, compared with the ACLF survival group, the ACLF death group had significantly higher expressions of pro-inflammatory cytokines (e.g., IL-6) and their receptors, chemokines (e.g., CCL4 and CCL5), and inflammation-inducing factors (e.g., HES4). Additionally, validation using scRNA-seq and flow cytometry revealed the presence of a cell type-specific transcriptional signature of pro-inflammatory monocytes THBS1, whose production might reflect the disease progression and poor prognosis. CONCLUSIONS: We present the accurate classification, molecular markers, and signaling pathways of monocytes associated with ACLF progression. Therapies targeting pro-inflammatory monocytes may be a promising approach for blocking ACLF progression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12072-022-10472-y.