Research ArticleFibrosis

Combinatorial targeting of TSLP, IL-25, and IL-33 in type 2 cytokine–driven inflammation and fibrosis

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Science Translational Medicine  04 May 2016:
Vol. 8, Issue 337, pp. 337ra65
DOI: 10.1126/scitranslmed.aaf1938

Teaming up against inflammation and fibrosis

The cult of the individual extends to new therapies—new targets are identified and validated (or not) on a one-on-one basis. However, no protein is an island, and failure with a monotherapy does not invalidate a target. Now, Vannella et al. demonstrate that this is indeed the case for some types of progessive type 2 inflammation and fibrosis. Using a variety of models including helminth infection and allergic lung inflammation, the authors show that individual disruption of the type 2 inflammatory molecules thymic stromal lymphopoietin (TLSP), interleukin-25 (IL-25), and IL-33 had no effect on the progression of type 2–dependent inflammation or fibrosis. However, targeting all three simultaneously blocked disease development and progression.


Thymic stromal lymphopoietin (TSLP), interleukin-25 (IL-25), and IL-33 are important initiators of type 2–associated mucosal inflammation and immunity. However, their role in the maintenance of progressive type 2 inflammation and fibrosis is much less clear. Using chronic models of helminth infection and allergic lung inflammation, we show that collective disruption of TSLP, IL-25, and IL-33 signaling suppresses chronic and progressive type 2 cytokine–driven inflammation and fibrosis. In a schistosome lung granuloma model or during chronic Schistosoma mansoni infection in the liver, individual ablation of TSLP, IL-25, or IL-33/ST2 had no impact on the development of IL-4/IL-13–dependent inflammation or fibrosis. However, significant reductions in granuloma-associated eosinophils, hepatic fibrosis, and IL-13–producing type 2 innate lymphoid cells (ILC2s) were observed when signaling of all three mediators was simultaneously disrupted. Combined blockade through monoclonal antibody (mAb) treatment also reduced IL-5 and IL-13 expression during primary and secondary granuloma formation in the lungs. In a model of chronic house dust mite–induced allergic lung inflammation, combined mAb treatment did not decrease established inflammation or fibrosis. TSLP/IL-33 double-knockout mice treated with anti–IL-25 mAb during priming, however, displayed decreased inflammation, mucus production, and lung remodeling in the chronic phase. Together, these studies reveal partially redundant roles for TSLP, IL-25, and IL-33 in the maintenance of type 2 pathology and suggest that in some settings, early combined targeting of these mediators is necessary to ameliorate progressive type 2–driven disease.

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