CD14 deficiency enhances Th2 responses and alternative activation of macrophages in response to schistosome infection or IL-4. (117.10)

Abstract

Abstract Prior to exposure to helminth antigens or helminth infection, the resting state of antigen presenting cells (APCs) plays a crucial role in their function in driving CD4+ Th2 immune bias. Whether or not APC innate receptors regulate alternative activation of APCs is not well understood. To test this, we injected schistosome eggs, or schistosome infected wild-type (WT) and CD14 -/- mice and examined evolution of Th2-type responses and alternative activation of macrophages. In response to schistosome infection, or exposure to schistosome eggs, CD14 negatively regulates Th2 responses and alternative activation of macrophages (AAMϕ). CD14-/- mice had enhanced production of CD4+ specific IL-4, IL-5 and IL-13 and increased numbers of regulatory T-cells. Livers of schistosome infected CD14-/- mice had elevated levels of AAMϕs, increased granuloma size with increased collagen deposition compared to WT counterparts. Q-PCR analysis showed significantly increased levels of Ym1, Fizz1 and Arg1 in livers of schistosome infected CD14-/- mice compared to WT controls. CD14 -/- mice injected with Lewis X glycoconjugate or IL-4 also showed significant increase in expansion of AAMϕs. Furthermore, in-vitro studies showed that enhanced alternative activation in response to IL-4 was independent of STAT-6 mediated signaling, suggesting that CD14 regulates both glycan and IL-4 induced alternative activation of macrophages through an unknown mechanism/pathway.