Toll-like Receptor 4-Dependent activation of Dendritic cells by heme binding protein from Ascaris suum (90.9)

Abstract

Abstract Toll-like receptors (TLRs) recognize specific molecular patterns on invading pathogens leading to the development of host immunity. A number of pathogens including helminths have used pattern recognition by TLRs to modulate host immunity and inflammation to establish a chronic infection. To understand the molecular basis for the TLR-induced tolerance induction observed in individuals infected with helminth parasites, we have established a mouse model combining allergic inflammation and Ascaris suum infection. These in vivo studies demonstrated that concomitant infection with chronic A. suum can inhibit allergic inflammation in response to a non-parasite allergen, ragweed (RW). In the current study, we have purified heme-binding protein (HBP) from pseudocoelomic fluid of A.suum and studied its antigenic and immunomodulatory properties using bone marrow derived dendritic cells. Recognition of HBP by antiserum from pigs infected with Ascaris larvae indicate that HBP is one of the antigenic proteins present in PCF. Furthermore, HBP exposure increases activation marker surface expression on DC including CD40, CD86 and MHC II. This increase in activation marker expression is abrogated in TLR4, but not TLR2, knockout mice implicating that HBP is a TLR4 ligand. Pretreatment of dendritic cells with HBP prior to LPS stimulation results in increased production of IL-10 but not IL-12 compared with DC exposed to LPS alone. These results provide the first evidence for a novel TLR4-mediated response to Ascaris suum HBP resulting in altered APC activation and cytokine production.