PAI1 mediates fibroblast-mast cell interactions in skin fibrosis

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  • Neha Pincha, Institute for Stem Cell Biology and Regenerative Medicine, Manipal University
  • ,
  • Edries Yousaf Hajam, Institute for Stem Cell Biology and Regenerative Medicine, Technology and Research Academy (SASTRA) University
  • ,
  • Krithika Badarinath, Institute for Stem Cell Biology and Regenerative Medicine, GKVK post
  • ,
  • Surya Prakash Rao Batta, Institute for Stem Cell Biology and Regenerative Medicine
  • ,
  • Tafheem Masudi, Institute for Stem Cell Biology and Regenerative Medicine
  • ,
  • Rakesh Dey, Institute for Stem Cell Biology and Regenerative Medicine
  • ,
  • Peter Andreasen
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  • Toshiaki Kawakami, La Jolla Institute for Allergy and Immunology, RIKEN
  • ,
  • Rekha Samuel, Center for Stem Cell Research
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  • Renu George, Venereology and Leprosy
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  • Debashish Danda, Department of Rheumatology
  • ,
  • Paul Mazhuvanchary Jacob, Christian Medical College, Vellore
  • ,
  • Colin Jamora, Institute for Stem Cell Biology and Regenerative Medicine

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.

OriginalsprogEngelsk
TidsskriftJournal of Clinical Investigation
Vol/bind128
Nummer5
Sider (fra-til)1807-1819
Antal sider13
ISSN0021-9738
DOI
StatusUdgivet - 1 maj 2018

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