IL-13 Activates a Mechanism of Tissue Fibrosis That Is Completely TGF-β Independent

Abstract

Fibrosis is a characteristic feature in the pathogenesis of a wide spectrum of diseases. Recently, it was suggested that IL-13-dependent fibrosis develops through a TGF-β1 and matrix metalloproteinase-9-dependent (MMP-9) mechanism. However, the significance of this pathway in a natural disorder of fibrosis was not investigated. In this study, we examined the role of TGF-β in IL-13-dependent liver fibrosis caused by Schistosoma mansoni infection. Infected IL-13−/− mice showed an almost complete abrogation of fibrosis despite continued and undiminished production of TGF-β1. Although MMP-9 activity was implicated in the IL-13 pathway, MMP-9−/− mice displayed no reduction in fibrosis, even when chronically infected. To directly test the requirement for TGF-β, studies were also performed with neutralizing anti-TGF-β Abs, soluble antagonists (soluble TGF-βR-Fc), and Tg mice (Smad3−/− and TGF-βRII-Fc Tg) that have disruptions in all or part of the TGF-β signaling cascade. In all cases, fibrosis developed normally and with kinetics similar to wild-type mice. Production of IL-13 was also unaffected. Finally, several genes, including interstitial collagens, several MMPs, and tissue inhibitors of metalloprotease-1 were up-regulated in TGF-β1−/− mice by IL-13, demonstrating that IL-13 activates the fibrogenic machinery directly. Together, these studies provide unequivocal evidence of a pathway of fibrogenesis that is IL-13 dependent but TGF-β1 independent, illustrating the importance of targeting IL-13 directly in the treatment of infection-induced fibrosis.

Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure

“…One possible explanation is the failure to transition from a Th1 type of response to a Th2 type of response, as has been proposed by a number of recent fibrosis models (28,31,34). Consistent with this possibility are studies that implicated CD204 involvement in the regulation of IL-12 release from AM (7,30).…”

IL-13 Receptor α2 Selectively Inhibits IL-13-Induced Responses in the Murine Lung

“…Studies in a variety of systems have demonstrated that IL-13 is a major mediator of these fibrotic responses (42,51,56). A number of studies demonstrated that IL-13 causes tissue fibrosis, at least in part, by inducing and activating TGF-␤1 (22,32), which is dependent on MCP-1/CCL2 and MMP-9, respectively (30,32).…”

Contribution of myeloid cell subsets to liver fibrosis in parasite infection

“…Yet, at this stage, despite granuloma involution as eggs are killed and the development of hyporesponsiveness in Th2 cells [47], the Th2/M2 inflammatory response elicits tissue remodelling, including induction of matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and collagens, that culminates in life-threatening liver and intestinal fibrosis, portal hypertension and haemorrhages (16-20 wkpi) [28,38,41,[48][49][50]. IL-13, via the IL-13Rα1/IL-4Rα receptor, is the most important fibrotic agent in schistosomiasis, with additive effects of IL-4, IL-5, IL-10 and IL-21 but not of TGFβ [45,[50][51][52][53]. Consequently, distinct collaborative IL-13 regulatory pathways that suppress the Th2/M2 activation and hamper fibrosis progression have been identified: the high-affinity IL-13 decoy receptor (IL-13Rα2) expressed by stromal cells; IL-12/IL-23p40 produced by macrophages and DCs driving the Th1/Th17 response; and IL-10 produced by M2 and regulatory T cells [46,[54][55][56][57][58][59].…”