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Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion

Nature Immunology volume 15, pages 938–946 (2014)Cite this article

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Abstract

We examined the role of innate cells in acquired resistance to the natural murine parasitic nematode, Nippostrongylus brasiliensis. Macrophages obtained from lungs as late as 45 d after N. brasiliensis inoculation were able to transfer accelerated parasite clearance to naive recipients. Primed macrophages adhered to larvae in vitro and triggered increased mortality of parasites. Neutrophil depletion in primed mice abrogated the protective effects of transferred macrophages and inhibited their in vitro binding to larvae. Neutrophils in parasite-infected mice showed a distinct transcriptional profile and promoted alternatively activated M2 macrophage polarization through secretory factors including IL-13. Differentially activated neutrophils in the context of a type 2 immune response therefore prime a long-lived effector macrophage phenotype that directly mediates rapid nematode damage and clearance.

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Figure 1: Eosinophils and macrophages surround parasitic larvae in the lung, and type 2 related cytokines are upregulated shortly after secondary inoculation with N. brasiliensis.
Figure 2: Macrophages from mice primed with N. brasiliensis directly damage larvae.
Figure 3: IL-4R signaling is required for resistance to N. brasiliensis mediated by primed macrophages.
Figure 4: Neutrophils are required for differentiation of effector M2 lung macrophages after primary inoculation with N. brasiliensis.
Figure 5: Depletion of neutrophils impairs effector lung macrophage polarization after primary inoculation.
Figure 6: N.brasiliensis–primed neutrophils show a distinct profile of gene expression.
Figure 7: N.brasiliensis–primed neutrophils polarize to an alternatively activated neutrophil phenotype that promotes M2 macrophage differentiation in vitro.

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Acknowledgements

Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture (USDA). The USDA is an equal opportunity provider and employer. Supported by National Institutes of Health (1R01AI107588 to W.C.G. and C.C.K.; 5R01AI031678 to W.C.G.; R00AI085035 to C.C.K.) and the Agricultural Research Service of the USDA (1235-51000-058 to J.F.U. Jr.).

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Authors and Affiliations

  1. Center for Immunity and Inflammation, New Jersey Medical School, Rutgers—The State University of New Jersey, Newark, New Jersey, USA

    Fei Chen, Wenhui Wu, Ariel Millman, Nirav Patel & William C Gause

  2. Department of Medicine, New Jersey Medical School, Rutgers—The State University of New Jersey, Newark, New Jersey, USA

    Fei Chen, Wenhui Wu, Ariel Millman, Nirav Patel & William C Gause

  3. Department of Medicine, Division of Experimental Medicine University of California, San Francisco, California, USA

    Joshua F Craft, Eunice Chen & Charles C Kim

  4. Laboratoire de Chimie et Biochimie, Pharmacologiques et Toxicologiques, Paris, France

    Jean L Boucher

  5. US Department of Agriculture, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Agricultural Research Service, Beltsville, Maryland, USA

    Joseph F Urban Jr

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Contributions

W.C.G., F.C., C.C.K. and J.F.U. Jr. designed the experiments; F.C., W.W., A.M., J.F.C., E.C. and N.P. did the experiments; J.L.B. prepared and provided the BEC; and W.C.G., F.C., W.W. and C.C.K. wrote the manuscript.

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Correspondence to William C Gause.

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Integrated supplementary information

Supplementary Figure 1 Nippostrongylus brasiliensis (Nb) migratory larvae induce long-term changes in immune cell populations.

At specific timepoints after Nb inoculation, mice were examined for changes in lung immune cell populations. (a) Representative haematoxylin and eosin staining of formalin-fixed lung sections (left small panels, scale bars, 20 μm; right panel, scale bar, 2 μm). Arrows indicate macrophages (Mac) and eosinophils (Eo), BV=blood vessel. (b) The numbers of lung immune cell populations obtained from a single lung lobule were determined by flow cytometry assay using antibodies specific for macrophages (F4/80+, CD11cvar, MHCIIint-hi), eosinophils (Siglec F+, MHCIIlo, CD11clo), neutrophils (Ly6G+), CD4+ T cells (CD3+CD4+), and CD8+ T cells (CD3+CD8+). Individual timepoints represent pooled samples from five mice per treatment group. (c) At three months after primary inoculation, mice were challenged and then examined at days two, four, and seven after secondary inoculation. The numbers of lung innate immune cells obtained from a single lung lobule was determined by flow cytometry (1° Nb, primary infection; 2° Nb, secondary infection). Individual timepoints represent pooled samples from five mice per treatment group. Similar results were obtained in two independent experiments.

Supplementary Figure 2 N. brasiliensis (Nb)-primed macrophages promote type 2 immune responses in lung.

(a) Macrophages (F4/80+, MHCII+, CD11c var) were electronically sorted from lung of Nb-inoculated mice and purity, including depletion of eosinophils, confirmed by G-W staining. (b) Nb-inoculated mice were sacrificed at day 7 and lung macrophages were sorted, labeled with CFSE, and transferred to recipient mice, to confirm the presence of transferred macrophages in the lung at day 3; (c) Total numbers of macrophages (F4/80+, CD11cvar, MHCIIint-hi), eosinophils (Siglec F+, MHCIIlo, CD11clo), and neutrophils (Ly6G+) in single lung lobule at day 2 and 3 after inoculation of recipient mice with transferred primed macrophages or control mice not receiving macrophage transfer. Individual timepoints represent values for pooled samples from 5 mice/treatment group; (d) and (e) as in (c), but lung tissue mRNA levels of: (d) Il4, Il5, Il13, and Il10 and (e) M2/M1 markers (Arg1, Chi3l3, and Nos2), as determined by qPCR. Gene expression is presented as the fold increase over naive WT controls after normalization to 18sRNA. Data shown for mRNA levels are the mean and SEM from five individual mice per group and are representative of two independent experiments. (f) Lung macrophages(F4/80hiMHCIIint-hiCD11cvar) were electronically sorted from mice at day 7 after Nb inoculation or were isolated from naive mice, transferred to recipient mice and two later inoculated with Nb; 2 days after Nb inoculatoin parasites were enumerated in the skin, as previously described23. (g) Lung macrophages were electronically sorted at day 7 after Nb inoculation or were isolated from naive mice, transferred to recipient mice, which were inoculated with Nb 2 days later. Five days after Nb inoculation parasites were enumerated in the gut. (h) Wild type and Jh–/– donor mice were inoculated with Nb and, at day 45 after inoculation, electronically sorted macrophages were transferred to naive recipient mice which were inoculated with Nb two days later. parasites were enumerated at five days post inoculation in the gut. (f-h) The mean and SEM of 5 individual mice per treatment group is shown and each experiment was repeated two times with similar results. *p<0.05.

Supplementary Figure 3 Effects of neutrophil depletion on lung and blood immune cell populations and on lung cytokine gene expression.

(a and b) Cell subpopulations at day 2 from the lung and blood of mice administered neutrophil-depleting anti-Ly6G antibody or isotype control at days -1 after N. brasiliensis inoculation. Data shown are mean of pooled samples from 3 mice per group, and this experiment was repeated two times with similar results. (c and d) Lung tissue from a single lung lobule was analyzed for changes in cytokine and M2 marker expression, by qPCR, at day 7 (c) or at day 1(d) after Nb inoculation and treatment with neutrophil depleting anti-Ly6G antibody or isotype control day -1, +3 (c) or day -1 (d). Gene expression is presented as the fold increase over naive WT controls after normalization to 18sRNA. Data shown are the mean and SEM from five individual mice per group and are representative of two independent experiments. *p<0.01

Supplementary Figure 4 Analysis of sorted neutrophils and the impact of CD4+ T cells on neutrophil recruitment to the lung during N. brasiliensis infection.

(a-b) Mice were infected with N. brasiliensis for 2 days and lung cell suspension collected for further analysis. (a) Gated CD11b+, LY6G+ neutrophil population selected for FACS sorting. (b) Frequency of basophils (FcɛRI+DX5+) was examined in total lung cells, the gated CD11b+Ly6G+ cell population, and electronically sorted CD11b+Ly6G+ cells. (c) Antibodies against CD4+ T cells were administered to BALB/c mice (800 µg, i.p.) 2 days before N. brasiliensis infection. Mice were sacrificed at day 2 and lung CD4+ T cells (CD3+CD4+) and neutrophils (CD11b+Ly6G+) were examined by flow analysis. Data were obtained from pool samples from 3 mice per group, and this experiment was repeated 3 times with similar results.

Supplementary Figure 5 Neutrophils, but not macrophages and CD4+ T cells are the source of IL-13 and IL-33 in the lung during N. brasiliensis infection at an early time point.

Mice were infected with N. brasiliensis for 2 days and then sacrificed. Whole lung cells from N. brasiliensis-infected mice at day 2 were stimulated by PMA/ion then stained with antibodies against cell surface marker CD3, CD4, CD11b, Ly6G, F4/80, and cytokines IL-13, IL-33. The expression of IL-13 and IL-33 on neutrophils, macrophages, or CD4+ T cells was examined by flow cytometry analysis. The flow plot is a representative of three mice per group, and the cell number graph is shown as mean and SEM from 3 individual mice per group and are representative of two independent experiments. *p<0.01

Supplementary Figure 6 Model of macrophage-mediated acquired resistance to the nematode parasite N. brasiliensis (Nb).

Initial Nb infection results in neutrophil infiltration of the lung within 2 days after inoculation. By day 4, the type 2 immune response develops, which includes alternatively activated neutrophil (N2) that then help promote the development of an anti-helminth effector macrophage phenotype, which develops by 7 days after inoculation and is sustained as a long-lived persistent phenotype capable of mediating accelerated parasite killing after secondary inoculation. These effector macrophages adhere to parasites through ITGAM-dependent mechanisms and mediate larval parasite damage and killing through mechanisms dependent on Arg1.

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Chen, F., Wu, W., Millman, A. et al. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat Immunol 15, 938–946 (2014). https://doi.org/10.1038/ni.2984

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