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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 5

PAI1-mediated fibroblast–mast cell adhesion leads to activation of both cell types.

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PAI1-mediated fibroblast–mast cell adhesion leads to activation of both ...
Skin sections from neonatal WT, Snail-Tg, and Snail-Tg/Pai1-KO animals were analyzed for (A) IHC of α-SMA expression (scale bar: 50 μm; n = 3) and (B) quantitation of Ki67 expression in vimentin+ fibroblasts (DF) (n = 3). (C and D) Buffer- or recombinant PAI1–treated fibroblast mast cell (MC) cocultures were analyzed for (C) α-SMA expression after 24 hours of treatment (scale bar: 50 μm; n = 3) and (D) Ki67 expression after 24 and 36 hours of treatment (n = 3). (E) Quantification of collagen contraction after 24 hours by fibroblasts, fibroblast–mast cell cocultures, and recombinant PAI1–treated fibroblast–mast cell cocultures (n = 4). (F) Giemsa staining of mast cells in neonatal WT, Snail-Tg, and Snail-Tg/Pai1-KO pup skin sections (scale bar: 10 μm; n = 4). (G) qPCR for Il4 and Il13 expression in fibroblast-adherent mast cells after 24 hours of treatment with recombinant PAI1 (n = 3). (H and I) Fibroblasts treated for 24 or 36 hours with conditioned media (CM) from fibroblast–mast cell cocultures in the presence or absence of recombinant PAI1 were analyzed for (H) α-SMA expression, with a 24-hour coculture as a positive control (scale bar: 50 μm; n = 3). (I) Quantitation of Ki67 expression (n = 3). Data represent the mean ± SEM. P values were calculated by Student’s t test (G) and 1-way ANOVA followed by Tukey’s post hoc analysis (B, D, E, and I) (*P < 0.05, **P < 0.01, and ***P < 0.001).

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