Dataset Information

Elevated Fibronectin Levels in Profibrotic CD14⁺ Monocytes and CD14⁺ Macrophages in Systemic Sclerosis.

ABSTRACT:

Background

Systemic sclerosis (SSc) is an autoimmune disease characterized by overproduction of extracellular matrix (ECM) and multiorgan fibrosis. Animal studies pointed to bone marrow-derived cells as a potential source of pathological ECM-producing cells in immunofibrotic disorders. So far, involvement of monocytes and macrophages in the fibrogenesis of SSc remains poorly understood.

Methods and results

Immunohistochemistry analysis showed accumulation of CD14⁺ monocytes in the collagen-rich areas, as well as increased amount of alpha smooth muscle actin (αSMA)-positive fibroblasts, CD68⁺ and mannose-R⁺ macrophages in the heart and lungs of SSc patients. The full genome transcriptomics analyses of CD14⁺ blood monocytes revealed dysregulation in cytoskeleton rearrangement, ECM remodeling, including elevated FN1 (gene encoding fibronectin) expression and TGF-β signalling pathway in SSc patients. In addition, single cell RNA sequencing analysis of tissue-resident CD14⁺ pulmonary macrophages demonstrated activated profibrotic signature with the elevated FN1 expression in SSc patients with interstitial lung disease. Peripheral blood CD14⁺ monocytes obtained from either healthy subjects or SSc patients exposed to profibrotic treatment with profibrotic cytokines TGF-β, IL-4, IL-10, and IL-13 increased production of type I collagen, fibronectin, and αSMA. In addition, CD14⁺ monocytes co-cultured with dermal fibroblasts obtained from SSc patients or healthy individuals acquired a spindle shape and further enhanced production of profibrotic markers. Pharmacological blockade of the TGF-β signalling pathway with SD208 (TGF-β receptor type I inhibitor), SIS3 (Smad3 inhibitor) or (5Z)-7-oxozeaenol (TGF-β-activated kinase 1 inhibitor) ameliorated fibronectin levels and type I collagen secretion.

Conclusions

Our findings identified activated profibrotic signature with elevated production of profibrotic fibronectin in CD14⁺ monocytes and CD14⁺ pulmonary macrophages in SSc and highlighted the capability of CD14⁺ monocytes to acquire a profibrotic phenotype. Taking together, tissue-infiltrating CD14⁺ monocytes/macrophages can be considered as ECM producers in SSc pathogenesis.

SUBMITTER: Rudnik M

PROVIDER: S-EPMC8421541 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cytokines are major players regulating immune responses toward inflammatory and tolerogenic results. In organ and bone marrow transplantation, new reagents are needed to inhibit tissue destructive mechanisms and eventually induce immune tolerance without overall immunosuppression. IL-34 is a cytokine with no significant homology with any other cytokine but that acts preferentially through CSF-1R, as CSF-1 does, and through PTPζ and CD138. Although IL-34 and CSF-1 share actions, a detailed analysis of their effects on immune cells needs further research. We previously showed that both CD4+ and CD8+ FOXP3+ Tregs suppress effector T cells through the production of IL-34, but not CSF-1, and that this action was mediated through antigen-presenting cells. We showed here by single-cell RNAseq and cytofluorimetry that different subsets of human monocytes expressed different levels of CSF-1R, CD138, and PTPζ and that both CD4+ and CD8+ FOXP3+ Tregs expressed higher levels of CSF-1R than conventional T cells. The effects of IL-34 differed in the survival of these different subpopulations of monocytes and RNAseq analysis showed several genes differentially expressed between IL-34, CSF-1, M0, M1, and also M2 macrophages. Acute graft-vs.-host disease (aGVHD) in immunodeficient NSG mice injected with human PBMCs was decreased when treated with IL-34 in combination with an anti-CD45RC mAb that depleted conventional T cells. When IL-34-differentiated monocytes were used to expand Tregs in vitro, both CD4+ and CD8+ FOXP3+ Tregs were highly enriched and this effect was superior to the one obtained with CSF-1. Human CD8+ Tregs expanded in vitro with IL-34-differentiated allogeneic monocytes suppressed human immune responses in an NSG mouse aGVHD model humanized with hPBMCs. Overall, we showed that IL-34 induced the differentiation of human monocytes with a particular transcriptional profile and these cells favored the development of potent suppressor FOXP3+ Tregs.

Dataset Information

Elevated Fibronectin Levels in Profibrotic CD14⁺ Monocytes and CD14⁺ Macrophages in Systemic Sclerosis.

Background

Methods and results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Elevated Fibronectin Levels in Profibrotic CD14+ Monocytes and CD14+ Macrophages in Systemic Sclerosis.

Background

Methods and results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Elevated Fibronectin Levels in Profibrotic CD14⁺ Monocytes and CD14⁺ Macrophages in Systemic Sclerosis.