Dataset Information

Role of the co-stimulatory molecule inducible T-cell co-stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction-associated steatohepatitis.

ABSTRACT:

Background and aims

Inducible T-cell Co-Stimulator (ICOS) present on T-lymphocytes and its ligand ICOSL expressed by myeloid cells play multiple roles in regulating T-cell functions. However, recent evidence indicates that reverse signalling involving ICOSL is also important in directing the differentiation of monocyte-derived cells. In this study, we investigated the involvement of ICOS/ICOSL dyad in modulating macrophage functions during the evolution of metabolic dysfunction-associated steatohepatitis (MASH).

Results

In animal models of MASH, ICOS was selectively up-regulated on CD8⁺ T-cells in parallel with an expansion of ICOSL-expressing macrophages. An increase in circulating soluble ICOSL was also evident in patients with MASH as compared to healthy individuals. ICOSL knockout (ICOSL^-/-) mice receiving choline/methionine deficient (MCD) diet for 6 weeks had milder steatohepatitis than wild type mice. MASH improvement was confirmed in mice fed with cholesterol-enriched Western diet for 24 weeks in which ICOSL deficiency greatly reduced liver fibrosis along with the formation of crown-like macrophage aggregates producing the pro-fibrogenic mediators osteopontin (OPN) and galectin-3 (Gal-3). These effects associated with a selective shewing of F4-80⁺/CD11b^high monocyte-derived macrophages (MoMFs) expressing the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) to CD11b^low/F4-80⁺ cells positive for the Kupffer cell marker C-type lectin-like type 2 receptor (CLEC-2), thus indicating an increased MoMF maturation toward monocyte-derived Kupffer cells.

Conclusions

These results suggest that CD8⁺ T-cells interaction with monocyte-derived macrophages through ICOS/ICOSL critically supports a specific subset of TREM2⁺-expressing cells contributing to the evolution of steatohepatitis. The data also point ICOS/ICOSL dyad as a possible target for therapeutic interventions in MASH.

SUBMITTER: Provera A

PROVIDER: S-EPMC10702974 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Role of the co-stimulatory molecule inducible T-cell co-stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction-associated steatohepatitis.

Provera Alessia A Ramavath Naresh Naik NN Gadipudi Laila Lavanya LL Gigliotti Casimiro Luca CL Boggio Elena E Vecchio Cristina C Stoppa Ian I Rolla Roberta R Boldorini Renzo R Pirisi Mario M Smirne Carlo C Albano Emanuele E Dianzani Umberto U Sutti Salvatore S

Frontiers in immunology 20231122

<h4>Background and aims</h4>Inducible T-cell Co-Stimulator (ICOS) present on T-lymphocytes and its ligand ICOSL expressed by myeloid cells play multiple roles in regulating T-cell functions. However, recent evidence indicates that reverse signalling involving ICOSL is also important in directing the differentiation of monocyte-derived cells. In this study, we investigated the involvement of ICOS/ICOSL dyad in modulating macrophage functions during the evolution of metabolic dysfunction-associate ...[more]

PMID: 38077334

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Project description:BackgroundIt has been shown that certain severe and refractory asthma cases are caused by neutrophil and not eosinophil infiltration. Inducible costimulatory molecular ligand (ICOSL) expression is closely associated with tumor and autoimmune diseases, yet a limited amount of data has been published regarding the significance of ICOSL in children with neutrophilic asthma. The present study aimed to explore the clinical significance of abnormal expression of ICOSL in peripheral blood and bronchoalveolar lavage fluid (BALF) samples of children with neutrophilic asthma.MethodsSelected children from the Children's Hospital of Soochow University who met the diagnostic criteria of asthma and excluded patients with a pathogen-positive etiology. Children who were admitted to the hospital for foreign body inhalation in the same period acted as the control group. Children with more than 50% of neutrophils in BALF samples were assigned to the neutrophilic asthma group (NA group), and the remaining subjects composed the asthma group (A group). The expression levels of ICOSL, IL-4, IL-17, IFN-γ, neutrophil elastase (NE), and matrix metalloproteinase-9 (MMP-9) were detected in plasma and BALF samples by enzyme-linked immunosorbent assays, in order to analyze the differences in the levels of cytokines and clinical characteristics between children with neutrophilic asthma and non-neutrophilic asthma. Moreover, the potential mechanism of ICOSL in neutrophilic asthma was explored.Results32 children were enrolled: 12 children in the NA group and 20 children in the A group. The mean hospitalization time of the NA group was longer than that of the A group (P<0.05). The concentration levels of ICOSL, IL-17, NE, and MMP-9 in plasma and BALF samples in the NA group were higher than those in the A group, while the levels of IFN-γ exhibited opposite. A significant correlation was found between ICOSL and IL-17 levels in plasma (r=0.753, P=0.012) and BALF (r=0.774, P=0.009) samples in the NA group.ConclusionsChildren with neutrophilic asthma were more severely affected, experiencing a considerably more difficult clinical treatment and longer hospitalization time. ICOSL may regulate the secretion of IL-17 by Th17 and increase the levels of NE and MMP-9, which are involved in the development of immune inflammation in neutrophils.

Dataset Information

Role of the co-stimulatory molecule inducible T-cell co-stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction-associated steatohepatitis.

Background and aims

Results

Conclusions

Publications

Role of the co-stimulatory molecule inducible T-cell co-stimulator ligand (ICOSL) in the progression of experimental metabolic dysfunction-associated steatohepatitis.

Similar Datasets

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