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J Clin Invest. 2018 May 1;128(5):1807-1819. doi: 10.1172/JCI99088. Epub 2018 Mar 26.

PAI1 mediates fibroblast-mast cell interactions in skin fibrosis.

Author information

1
IFOM-inStem Joint Research Laboratory, Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, Karnataka, India.
2
Manipal Academy of Higher Education, Manipal, Karnataka, India.
3
Shanmugha Arts, Science, Technology and Research Academy (SASTRA) University, Thanjavur, Tamil Nadu, India.
4
National Centre for Biological Sciences (NCBS), GKVK post, Bangalore, Karnataka, India.
5
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
6
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
7
Laboratory for Allergic Disease, RIKEN Center for Integrative Medical Sciences, Research Center for Allergy and Immunology (IMS-RCAI), Yokohama, Japan.
8
Department of Pathology, Center for Stem Cell Research.
9
Department of Dermatology, Venereology and Leprosy.
10
Department of Rheumatology, and.
11
Department of Surgery, Christian Medical College (CMC), Vellore, Tamil Nadu, India.

Abstract

Fibrosis is a prevalent pathological condition arising from the chronic activation of fibroblasts. This activation results from the extensive intercellular crosstalk mediated by both soluble factors and direct cell-cell connections. Prominent among these are the interactions of fibroblasts with immune cells, in which the fibroblast-mast cell connection, although acknowledged, is relatively unexplored. We have used a Tg mouse model of skin fibrosis, based on expression of the transcription factor Snail in the epidermis, to probe the mechanisms regulating mast cell activity and the contribution of these cells to this pathology. We have discovered that Snail-expressing keratinocytes secrete plasminogen activator inhibitor type 1 (PAI1), which functions as a chemotactic factor to increase mast cell infiltration into the skin. Moreover, we have determined that PAI1 upregulates intercellular adhesion molecule type 1 (ICAM1) expression on dermal fibroblasts, rendering them competent to bind to mast cells. This heterotypic cell-cell adhesion, also observed in the skin fibrotic disorder scleroderma, culminates in the reciprocal activation of both mast cells and fibroblasts, leading to the cascade of events that promote fibrogenesis. Thus, we have identified roles for PAI1 in the multifactorial program of fibrogenesis that expand its functional repertoire beyond its canonical role in plasmin-dependent processes.

KEYWORDS:

Cell Biology; Fibrosis; Inflammation; Innate immunity; Skin

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