Department of Biotechnology
inStem (Institute for Stem Cell Science and Regenerative Medicine)

PAI1 mediates fibroblast-mast cell interactions in skin fibrosis.

Publication Type

Research Support, N.I.H., Extramural

Date of Publication

May 1, 2018

Journal

The Journal of clinical investigation

Volume/Issue

128/5

ISSN

1558-8238

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.

Alternate Journal

J Clin Invest

PubMed ID

29584619

PubMed Central ID

PMC5919880

Authors

Neha Pincha
Edries Yousaf Hajam
Krithika Badarinath
Surya Prakash Rao Batta
Tafheem Masudi
Rakesh Dey
Peter Andreasen
Toshiaki Kawakami
Rekha Samuel
Renu George
Debashish Danda
Paul Mazhuvanchary Jacob
Colin Jamora

Keywords

Up-Regulation
Cell Communication
Animals
Epidermis
Intercellular Adhesion Molecule-1
Mice
Mast Cells
Mice, Knockout
Serpin E2
Fibroblasts
Skin Diseases
Fibrosis