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Acidic chitinase primes the protective immune response to gastrointestinal nematodes

Nature Immunology volume 17, pages 538–544 (2016)Cite this article

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Abstract

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103+ dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

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Figure 1: AMCase-deficient mice develop acute HDM-induced lung allergy despite diminished ILC2s.
Figure 2: Chronic HDM induces similar allergy in the lungs of wild-type and AMCase-deficient mice.
Figure 3: AMCase-deficient mice develop S. mansoni egg–induced lung granulomas.
Figure 4: AMCase is critical for type 2–mediated protection against N. brasiliensis.
Figure 5: Type 2 immunity against H. p. bakeri is impaired in AMCase-deficient mice.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank MedImmune for generating the anti-AMCase rabbit sera, C. Mainhart for genotyping, T. Gieseck and K. Kindrachuk for discussions, and the animal care staffs of Buildings 50 and 14BS at the US National Institutes of Health's Bethesda, Maryland campus for the conscientious care of mice.

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Authors and Affiliations

  1. Program in Tissue Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

    Kevin M Vannella, Thirumalai R Ramalingam, Kevin M Hart, Rafael de Queiroz Prado, Joshua Sciurba, Luke Barron, Lee A Borthwick, Margaret Mentink-Kane, Sandra White, Robert W Thompson, Allen W Cheever & Thomas A Wynn

  2. Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK

    Lee A Borthwick

  3. United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Center, Beltsville, Maryland, USA

    Allen D Smith & Joseph F Urban Jr

  4. Infectious Disease Pathology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA

    Kevin Bock & Ian Moore

  5. Inflammation and Immunity, Pfizer Worldwide R&D, Cambridge, Massachusetts, USA

    Lori J Fitz

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  1. Kevin M Vannella
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Contributions

K.M.V., T.R.R. and T.A.W. conceived and designed the experiments; K.M.V., A.D.S., K.M.H., L.A.B., R.W.T., S.W., J.F.U., R.d.Q.P. and J.S. performed the experiments; I.M. and K.B. performed immunofluorescence techniques; K.M.V., T.R.R., A.D.S., A.W.C., L.B., L.A.B., M.M.-K., T.A.W., J.F.U. and R.d.Q.P. analyzed the data; A.D.S., A.W.C., I.M., J.F.U. and L.J.F. contributed reagents; K.M.V., T.R.R. and T.A.W. wrote the paper.

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Correspondence to Thomas A Wynn.

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Integrated supplementary information

Supplementary Figure 1 Acute model of papain-induced type 2 allergic inflammation in the lung.

(a) Quantitative PCR analysis of gene expression in lung tissue from wild type mice or AMCase-KO mice sensitized and challenged intranasally with PBS (n = 3 mice per genotype) or papain (n =5 mice per genotype) expressed relative to water-treated wild type. (b) Quantification of eosinophils in lung tissue of mice in a (PBS: n = 3, papain: n = 5). (c) Intracellular cytokine analysis of lung tissue lymphocytes of mice in a (PBS: n = 3, HDM: n = 5). (d) Quantification of eosinophils in BALF of mice in a (PBS: n = 3, HDM: n = 5). (e) Intracellular cytokine analysis of BALF lymphocytes of mice in a (PBS: n = 3, HDM: n = 5). Error bars represent standard error of the mean, and each data point represents a value for an individual mouse.

Supplementary Figure 2 Acute model of SEA-induced type 2 allergic inflammation in the lung.

(a) Quantitative PCR analysis of gene expression in lung tissue from wild type mice or AMCase-KO mice sensitized and challenged intratracheally with PBS (n = 3 mice per genotype) or schistosoma egg antigen (SEA) (n = 9 mice per genotype) expressed relative to PBS-treated wild type. (b) Quantification of leukocytes in BALF of mice in a (PBS: n = 3, SEA: n = 6). (c) Intracellular cytokine analysis of lung tissue lymphocytes of mice in a (PBS: n = 3, WT/SEA: n = 9, KO/SEA: n = 5). (d) Quantification of eosinophils in lung tissue of mice in a (PBS: n = 3, WT/SEA: n = 9, KO/SEA: n = 5). Data are representative of three experiments with similar results. Error bars represent standard error of the mean, and each data point represents a value for an individual mouse.

Supplementary Figure 3 Gene expression in lung tissue during N. brasiliensis infection.

Quantitative PCR analysis of gene expression in lung tissue from wild type mice (n = 7) or AMCase-KO mice (n = 7) 8 days after primary infection with N. brasiliensis. Data shown relative to expression in lung tissue from naïve mice. *P<0.05 (Student’s t-test). Data are representative of two experiments with similar results. Error bars represent standard error of the mean, and each data point represents a value for an individual mouse.

Supplementary Figure 4 Wild type and AMCase-deficient T cells are equally competent at clearing H.p. bakeri infection.

Quantification of H.p. bakeri worms recovered from intestines of TCRα KO mice that were recipients of 2x105 T cells from previously infected wild type mice (triangles, n = 8), 2x105 T cells from previously infected AMCase-KO mice (squares, n = 3), or no T cells (circles, n = 4).

Supplementary Figure 5 Il33 expression in small intestine tissue 3.5 days after primary H. p. bakeri infection.

Quantitative PCR analysis of Il33 expression in proximal small intestine tissue from wild type mice or AMCase-KO mice 3.5 days post-infection (n = 9 per genotype) or from uninfected wild type or AMCase-KO (n = 3 per genotype). Error bars represent standard error of the mean, and each data point represents a value for an individual mouse.

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Vannella, K., Ramalingam, T., Hart, K. et al. Acidic chitinase primes the protective immune response to gastrointestinal nematodes. Nat Immunol 17, 538–544 (2016). https://doi.org/10.1038/ni.3417

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