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PAI1 mediates fibroblast–mast cell interactions in skin fibrosis
Neha Pincha, … , Paul Mazhuvanchary Jacob, Colin Jamora
Neha Pincha, … , Paul Mazhuvanchary Jacob, Colin Jamora
Published March 26, 2018
Citation Information: J Clin Invest. 2018;128(5):1807-1819. https://doi.org/10.1172/JCI99088.
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Research Article Cell biology Inflammation

PAI1 mediates fibroblast–mast cell interactions in skin fibrosis

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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.

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

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Figure 6

Model of the multiple roles of PAI1 in cutaneous fibrosis.

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Model of the multiple roles of PAI1 in cutaneous fibrosis.
PAI1 secreted...
PAI1 secreted from the Snail-Tg keratinocytes functions in 3 potentially novel roles during fibrogenesis. 1: PAI1 acts as a chemoattractant for the infiltration of mast cells into the skin. 2: PAI1 stimulates integrin signaling in dermal fibroblasts that leads to the upregulation of tenacin C and the establishment of an inflammatory microenvironment, which is a key driver of fibrogenesis. In addition, this signaling pathway also leads to the upregulation of ICAM1 expression, which renders the fibroblast competent to adhere to the mast cell. 3: This adhesion culminates in the cellular activation phase of fibrosis development. In addition to the direct activation of a subset of fibroblasts (marked by α-SMA expression and increased contractile behavior), this physical interaction results in the activation of the adherent mast cells. The activated mast cells (mast cell*) then secrete cytokines such as IL-4 and IL-13 capable of promoting the proliferation of another subset of fibroblasts.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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