The roles of eotaxin and the STAT6 signalling pathway in eosinophil recruitment and host resistance to the nematodes Nippostrongylus brasiliensis and Heligmosomoides bakeri

Abstract

Expulsion of adult Nippostrongylus brasiliensis worms from the small intestine is profoundly impaired in signal transducer and activator of transcription (STAT)6-deficient mice. IL-5 transgenic (Tg) mice with constitutive eosinophilia show profound early resistance in the skin and/or later pre-lung phase of primary infections with N. brasiliensis. This study was designed to assess the importance of the eosinophil chemokine eotaxin and the STAT6/interleukin (IL)-4/IL-13 signalling pathway in early resistance to N. brasiliensis. Eosinophil recruitment into the skin following injection of N. brasiliensis larvae was reduced in STAT6- or eotaxin-deficient/IL-5 Tg double mutant mice. While ablation of eotaxin did not impair resistance in the pre-lung phase of N. brasiliensis infections in IL-5 Tg mice, elimination of STAT6 caused a modest reduction in resistance in both primary and secondary infections on this genetic background. STAT6(-/-)-, IL-13(-/-)- and IL-4Ralpha(-/-)-deficient single mutant and IL-13(-/-)/IL-4Ralpha(-/-) double mutant mice were more susceptible than WT mice during the pre-lung phase of secondary N. brasiliensis infections. In contrast, primary or secondary resistance were unaffected at either the pre-lung or gut stages of infection in eotaxin(-/-) single mutant mice. STAT6(-/-) and eotaxin(-/-) mice with or without the IL-5 transgene, were no more susceptible than WT or IL-5 Tg mice to protracted primary infections with Heligmosomoides bakeri, a parasitic nematode that is restricted to the gut. Our data suggest that parasitic nematodes that transit through the skin and lungs en route to the gut may be susceptible to early (pre-lung) innate and adaptive immune mechanisms that are dependent on the STAT6/IL-4/IL-13 signalling pathway, and this may be important for the development of effective therapies and vaccines.

STAT6 regulates natural helper cell proliferation during lung inflammation initiated byAlternaria

“…Additionally, our previous studies demonstrated that bone marrow-derived cells expressing STAT6 are required for eosinophil accumulation after a single Alternaria challenge (7). Our current studies show that STAT6 is not required for NHC IL-5 production and suggest that other cell types may produce eosinophil chemoattractants, such as eotaxins, in a STAT6-dependent manner, which may be responsible for the reduction of eosinophils in STAT6 Ϫ/Ϫ mice (18,43,46). Thus NHCs are likely an important source of IL-13 that may subsequently induce STAT6-dependent eotaxin-1 and eotaxin-2 production in other cell types, such as dendritic cells and macrophages, that promote eosinophilia.…”

IL-33 drives biphasic IL-13 production for noncanonical Type 2 immunity against hookworms

“…Immunity against N. brasiliensis rechallenge was impaired in mice made eosinophil deficient by targeted deletion of the erythroid transcription factor (GATA-1) or IL-5 (27,28,43). Mechanistically, IL-33 could promote eosinophilic lung inflammation through inducing IL-5 and IL-13 production from CD4 + T cells and ILC2s (19), or by directly activating eosinophils through TI/ST2.…”

Resource limitation alters the consequences of co-infection for both hosts and parasites

“…Eosinophils are upregulated during Th2 responses, act as a white blood cell defence against helminth infections, and contribute to host resistance to N. brasiliensis and H. p. bakeri during primary and subsequent infections (Janeway, 2008;Knott et al, 2009). We quantified eosinophils by flow cytometry, which provides a quantitative estimate of the proportion of cells in the tissue that are eosinophils.…”