TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus

• Published in: PLoS pathogens Vol. 13; no. 7; p. e1006536
• Main Authors: Kannan, Yashaswini, Entwistle, Lewis J, Pelly, Victoria S, Perez-Lloret, Jimena, Walker, Alan W, Ley, Steven C, Wilson, Mark S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-07-2017; Public Library of Science (PLoS)
• Subjects: Allergies; Analysis; Animals; Autoimmunity; Biology and Life Sciences; CD11b antigen; CD11c antigen; CD4 antigen; Cell migration; Cellular signal transduction; Chemokine CCL24 - genetics; Chemokine CCL24 - immunology; Chemokines; Chemotaxis; Clonal deletion; Crick, Francis; Dendritic cells; Eosinophils; Epithelial cells; Expulsion; Extracellular signal-regulated kinase; Female; Fitness; Funding; Gene expression; Genes; Genomes; Helper cells; Homing; House dust; Housing; Humans; Hypersensitivity; Immune response; Immunity; Immunity, Innate; Infections; Inflammation; Innate immunity; Interleukin 1 receptors; Intestine; Kinases; Laboratories; Leukocyte migration; Leukocytes; Leukocytes (eosinophilic); Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Male; MAP kinase; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - immunology; Medical research; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Myeloid cells; Nematospiroides dubius - genetics; Nematospiroides dubius - immunology; Nematospiroides dubius - physiology; Neutralization; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - immunology; Respiratory tract; Rodents; Roles; Roundworm infections; Signal transduction; Stimulation; Strongylida Infections - enzymology; Strongylida Infections - genetics; Strongylida Infections - immunology; Strongylida Infections - parasitology; Th2 Cells - immunology; Tumor necrosis factor receptors
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006536

TPL-2 (COT, MAP3K8) kinase activates the MEK1/2-ERK1/2 MAPK signaling pathway in innate immune responses following TLR, TNFR1 and IL-1R stimulation. TPL-2 contributes to type-1/Th17-mediated autoimmunity and control of intracellular pathogens. We recently demonstrated TPL-2 reduces severe airway allergy to house dust mite by negatively regulating type-2 responses. In the present study, we found that TPL-2 deficiency resulted in resistance to Heligmosomoides polygyrus infection, with accelerated worm expulsion, reduced fecal egg burden and reduced worm fitness. Using co-housing experiments, we found resistance to infection in TPL-2 deficient mice (Map3k8-/-) was independent of microbiota alterations in H. polygyrus infected WT and Map3k8-/-mice. Additionally, our data demonstrated immunity to H. polygyrus infection in TPL-2 deficient mice was not due to dysregulated type-2 immune responses. Genome-wide analysis of intestinal tissue from infected TPL-2-deficient mice identified elevated expression of genes involved in chemotaxis and homing of leukocytes and cells, including Ccl24 and alternatively activated genes. Indeed, Map3k8-/-mice had a significant influx of eosinophils, neutrophils, monocytes and Il4GFP+ T cells. Conditional knockout experiments demonstrated that specific deletion of TPL-2 in CD11c+ cells, but not Villin+ epithelial cells, LysM+ myeloid cells or CD4+ T cells, led to accelerated resistance to H. polygyrus. In line with a central role of CD11c+ cells, CD11c+ CD11b+ cells isolated from TPL-2-deficient mice had elevated Ccl24. Finally, Ccl24 neutralization in TPL-2 deficient mice significantly decreased the expression of Arg1, Retnla, Chil3 and Ear11 correlating with a loss of resistance to H. polygyrus. These observations suggest that TPL-2-regulated Ccl24 in CD11c+CD11b+ cells prevents accelerated type-2 mediated immunity to H. polygyrus. Collectively, this study identifies a previously unappreciated role for TPL-2 controlling immune responses to H. polygyrus infection by restricting Ccl24 production.