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Title: Acidic Chitinase Limits Allergic Inflammation and Promotes Intestinal Nematode Expulsion

Author
item VANNELLA, KEVIN - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item RAMALINGAM, THIRUMALAI - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item DE QUEIROZ, PRADO - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item SCIURBA, J - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item BARRON, LUKE - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item BORTHWICK, LEE - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Smith, Allen
item MENTINK-KANE, MARGARET - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item WHITE, SANDRA - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item THOMPSON, ROBERT - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item CHEEVER, A - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item BOCK, K - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item MOORE, IAN - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item FITZ, L - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Urban, Joseph
item WYNN, T - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)

Submitted to: Nature Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/4/2016
Publication Date: 5/1/2016
Citation: Vannella, K.M., Ramalingam, T.R., De Queiroz, P.R., Sciurba, J., Barron, L., Borthwick, L., Smith, A.D., Mentink-Kane, M., White, S., Thompson, R.W., Cheever, A.W., Bock, K., Moore, I., Fitz, L.J., Urban Jr, J.F., Wynn, T.A. 2016. Acidic Chitinase Limits Allergic Inflammation and Promotes Intestinal Nematode Expulsion. Nature Immunology. 17(5):538-44 doi: 101038/ni.3417.

Interpretive Summary: An enzyme called AMCase that can break apart the structure of chitin, a component of the cell walls of fungi and the exoskeleton of insects, is markedly increased in certain cells found in the mucosal membranes in response to allergic inflammation and infection with parasitic worms, but its precise functional role is unclear. It has been shown, however, that antibodies that block this enzyme reduce allergic inflammation, suggesting the enzyme might represent a therapeutic target to control allergic asthma. Allergic inflammation has long been associated with allergic lung inflammation induced by allergens and also required for the development of immunity to parasitic worms. Consequently, most therapeutic strategies that decrease allergic inflammation lead to increased susceptibility to worms. We have now shown that AMCase represents a unique target in allergic inflammation in that its activity is associated with increased protection from allergic lung inflammation and protection from worm infection. Thus, therapeutic strategies that augment AMCase activity in the lung and the intestinal tract offer a unique approach to provide protection from allergic lung inflammation, while simultaneously enhancing immunity to worms. This information is important to those interested in controlling allergic inflammation and the spread of worm infection in both livestock and humans.

Technical Abstract: Acidic mammalian chitinase (AMCase) is stereotypically induced during mammalian immune responses to helminths and allergens—yet, its precise role in immunity and inflammation is unclear. Here we show that in the lung, genetic ablation of AMCase failed to diminish type 2 inflammation against helminth eggs and house dust mites, ruling out a categorical requirement for this enzyme in the initiation of type 2 responses. In fact, AMCase deficiency resulted in augmented airway inflammation and increased expression of the pro-fibrotic cytokine IL-13 in response to chronic house dust mite exposure. In contrast, AMCase-deficient mice displayed a prominent defect in mounting a protective type 2 immune response to the gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The decrease in immunity was associated with a marked reduction in mucus production and diminished expression of Il13, Chil3, Retnlb, and Clca3 mRNA in the gut. Together, these findings imply a dual evolutionary advantage for functional AMCase in mammals by limiting the pro-inflammatory effects of allergen exposure in the lung and by facilitating the development of protective type 2 immune responses to gastrointestinal nematodes.