A Novel Ligand of Toll-like Receptor 4 From the Sheath of Wuchereria bancrofti Microfilaria Induces Proinflammatory Response in Macrophages

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Lymphatic filariasis, frequently caused from <span style="font-style:italic;">Wuchereria bancrofti</span> infection, is endemic in several parts of the globe and responsible for human health problems and socioeconomic loss to a large extent. Inflammatory consequences originating from host–parasite interaction play a major role in the disease pathology and allied complications. The identity of the key mediator of this process is yet unknown in filarial research.<div class="boxTitle">Methods.</div>Microfilarial protein (MfP) was isolated from the sheath of <span style="font-style:italic;">W. bancrofti</span> microfilariae through ultrafiltration, followed by chromatographic separation. Expression of signaling molecules was studied by enzyme-linked immunosorbent assay and immunoblotting. Binding of MfP to Toll-like receptor 4 (TLR4) was determined by co-immunoprecipitation, fluorescein isothiocyanate-probing, and surface plasmon resonance analysis.<div class="boxTitle">Results.</div>We found that MfP (approximately 70 kDa) binds to macrophage-TLR4 and triggers nuclear factor kappa beta activation that upregulates secretion of proinflammatory cytokines. Microfilarial protein failed to induce inflammation in either TLR^KO macrophage or macrophage treated with TLR4 inhibitor, indicating that MfP acts through TLR4. We have also detected phenotypic transformation of macrophages from anti-inflammatory (M2) to proinflammatory (M1) subtype after incubation with MfP.<div class="boxTitle">Conclusions.</div>Microfilarial protein appears to be a new ligand of TLR4 from <span style="font-style:italic;">W. bancrofti</span>. Determination of its functional attributions in the host–parasite relationship, especially immunopathogenesis of filarial infection, may improve our understanding.</span>

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