TPL-2 restricts Ccl24-dependent immunity to Heligmosomoides polygyrus

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. © 2017 kannan et al.