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Chitinase-like proteins promote IL-17-mediated neutrophilia in a tradeoff between nematode killing and host damage
Tara E Sutherland1, Nicola Logan1, Dominik Rckerl1, Alison A Humbles2, Stuart M Allan3, Venizelos Papayannopoulos4, Brigitta Stockinger4, Rick M Maizels1 & Judith E Allen1
Enzymatically inactive chitinase-like proteins (CLPs) such as BRP-39, Ym1 and Ym2 are established markers of immune activation and pathology, yet their functions are essentially unknown. We found that Ym1 and Ym2 induced the accumulation of neutrophils through the expansion of gd T cell populations that produced interleukin 17 (IL-17). While BRP-39 did not influence neutrophilia, it was required for IL-17 production in gd T cells, which suggested that regulation of IL-17 is an inherent feature of mouse CLPs. Analysis of a nematode infection model, in which the parasite migrates through the lungs, revealed that the
IL-17 and neutrophilic inflammation induced by Ym1 limited parasite survival but at the cost of enhanced lung injury.
Our studies describe effector functions of CLPs consistent with innate host defense traits of the chitinase family.
npg 201 4 Nature America, Inc. All rights reserved.
Chitinase-like proteins (CLPs) are associated with a range of pathologies and are among the most abundant proteins found under conditions of type 2 activation of the immune system, but their functions remain poorly understood1. CLPs are members of a family that include both chitotriosidase and acidic mammalian chitinase, enzymes that cleave chitin, which is a widespread structural component of arthropods, parasites and fungi. Consistent with the function of chitinases throughout the evolutionary tree1, active chitinase enzymes act to defend the host against chitin-containing pathogens24. CLPs, however, are catalytically inactive due to loss-of-function mutations5. Evolutionarily recent gene-duplication events in mammals have resulted in expansion and diversification of the CLP-encoding genes such that each mammalian species exhibits a different array of CLP-encoding genes5. Mice have three CLPs (Ym1, Ym2 and BRP-39), while humans have two (YKL-39 and YKL-40). The rapid divergence of CLPs in mammalian species indicates a role for these proteins in host defense, but their expression patterns in many non-infectious settings1,6 precludes the possibility that defense against pathogens is their sole function.
The mouse proteins Ym1 (encoded by Chil3) and Ym2 (encoded by Chil4) were the first CLPs to be identified...