Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: There is accumulating evidence for a role of Wnt-signaling pathway activation in connective tissue disorders, including dermal and lung fibrosis. In particular, expression of WNT1-inducible signaling protein–1 (WISP1) is increased in human scleroderma skin and idiopathic pulmonary fibrosis (IPF) lung. A recent study showed that WISP-1 mediates lung fibrosis in mice. In the current study, we investigated the function of WISP-1 in dermal fibrosis.
Methods: There is accumulating evidence for a role of Wnt-signaling pathway activation in connective tissue disorders, including dermal and lung fibrosis. In particular, expression of WNT1-inducible signaling protein–1 (WISP1) is increased in human scleroderma skin and idiopathic pulmonary fibrosis (IPF) lung. A recent study showed that WISP-1 mediates lung fibrosis in mice. In the current study, we investigated the function of WISP-1 in dermal fibrosis.
Results: Anti-WISP-1 mAb treatment reduced skin fibrosis in the GVHD model, as documented by reduction of hydroxyproline content and Masson’s trichrome staining in skin at week 4 post-graft. Gene expression analysis showed a concomitant reduction of GVHD-associated Th2 responses in skin, including cytokine/receptor (IL-13, IL-4Rα) and chemokines (CCL2, CCL17 and CCL22). This Th2 profile reduction was associated with a broad-based reduction of the pro-Th2 TSLP-OX40L axis (TSLP, TSLPR, IL-7R, OX40L), suggesting that the TSLP/OX40L pathway may in part mediate the effect of WISP-1 on the Th2 response in GVHD. This view was supported with data generated from a separate study showing that anti-TSLP mAb treatment in GVHD-induced fibrosis reduces levels of Th2 (IL-13, IL-4) but not Th1 (IFN-γ) cytokines in skin and blood. TSLP neutralization also fully reduced GVHD-induced WISP-1 expression, further substantiating a functional link between WISP-1 and the TSLP/OX40L axis in fibrosis.
Conclusion: Consistent with the role of Wnt signaling pathways in fibrosis, WISP-1 neutralization reduces GVHD-induced skin fibrosis in part by affecting TSLP-OX40L-based Th2 responses. Interestingly, scleroderma shows increased dermal TSLP level and OX40L polymorphisms, suggesting that targeting WISP-1 may offer a valuable therapeutic strategy for the treatment of scleroderma and other skin fibrosis disorders.
Disclosure:
R. Lemaire,
None;
T. Burwell,
None;
R. Griffin,
None;
J. Bakken,
None;
J. Madary,
None;
L. Murray,
None;
R. Herbst,
None;
J. Connor,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/wisp-1-neutralization-reduces-gvhd-induced-skin-fibrosis-by-altering-tslp-ox40l-axis-dependent-th2-responses/