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

Abstract

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.

Approaching Thrombospondin-1 as a Potential Target for Mesenchymal Stromal Cells to Support Liver Regeneration after Partial Hepatectomy in Mouse and Humans

“…Besides its role as an attenuator of liver regeneration [ 12 ], THBS1 is seemingly involved in the pathogenesis of various liver diseases. In patients suffering from acute-on-chronic liver failure (ACLF), pro-inflammatory monocytes are a major source of THBS1 involved in disease progression [ 44 ]. THBS1 impacts on liver metabolism towards lipid storage, thus supporting the pathogenesis of MASH (Metabolic Dysfunction-Associated SteatoHepatitis) in rodents [ 45 , 46 ] and humans [ 47 , 48 , 49 ].…”

Thrombospondin 1 enhances systemic inflammation and disease severity in acute-on-chronic liver failure

“…In the progression of ACLF, elevated THBS1 levels could contribute to liver dysfunction, intensifying hepatic damage and cellular death through the activation of key pathways, such as TGF-β1 and NF-κB, thereby precipitating liver failure. Furthermore, THBS1 can stimulate the up-regulation of IL-1β, IL-6, and TNF-α in immune cells, potentially regulating cell differentiation and apoptosis by activating inflammatory cells [ 47 ]. Researchers were able to verify the involvement of THBS1 in various tissue injuries and inflammatory disorders [ 48 – 51 ], mainly through interactions with multiple targets and receptors, such as TGF-β, CD36, integrins and CD47 [ 11 , 52 ].…”

Hematological ratios in patients with acute decompensation and acute-on-chronic liver failure: prognostic factors

“…In addition, pro-inflammatory monocytes were closely related to ACLF progression. Monocytes can suppress lymphocyte activation and inhibit the local immune response [36].…”