Abstract
Human C-type lectin member 18A (CLEC18A) is ubiquitously expressed in human, and highest expression levels are found in human myeloid cells and liver. In contrast, mouse CLEC18A (mCLEC18A) is only expressed in brain, kidney and heart. However, the biological functions of CLEC18A are still unclear. We have shown that a single amino acid change (S339 →R339) in CTLD domain has profound effect in their binding to polysaccharides and house dust mite allergens. In this study, we further demonstrate that CLEC18A and its mutant CLEC18A(S339R) associate with TLR3 in endosome and bind poly (I:C) specifically. Compared to TLR3 alone, binding affinity to poly (I:C) is further increased in TLR3-CLEC18A and TLR3-CLEC18A(S339R) complexes. Moreover, CLEC18A and CLEC18A(S339R) enhance the production of type I and type III interferons (IFNs), but not proinflammatory cytokines, in response to poly (I:C) or H5N1 influenza A virus (IAV) infection. Compared to wild type (WT) mice, ROSA-CLEC18A and ROSA-CLEC18A(S339R) mice generate higher amounts of interferons and are more resistant to H5N1 IAV infection. Thus, CLEC18A is a TLR3 co-receptor, and may contribute to the differential immune responses to poly (I:C) and IAV infection between human and mouse.
Highlights
Human C-type lectin member 18A (CLEC18A) is ubiquitously expressed in human, and highest expression levels are found in human myeloid cells and liver
We found that macrophages and alveolar epithelial cells (AECs) from ROSA-CLEC18A and ROSA-CLEC18A(S339R) mice produce higher amounts of IFNs and IFNstimulated genes (ISGs) after incubation with poly (I:C) or H5N1 influenza A virus (IAV)
We found that HMW poly (I:C) and H5N1 IAV increased the efficiency of fluorescence resonance energy transfer (FRET) between TLR3CLEC18A, respectively (Fig. 4a, b)
Summary
Human C-type lectin member 18A (CLEC18A) is ubiquitously expressed in human, and highest expression levels are found in human myeloid cells and liver. Compared to wild-type (WT) mice, TLR3−/− mice produced lower levels of inflammatory mediators and displayed less cell infiltration after H3N2 influenza A virus (IAV) infection, despite higher virus titer being noted in the lung[6] This observation suggests that TLR3-mediated signaling prefers to induce proinflammatory cytokine release and has a detrimental effect in IAV infection in mice. ROSA-CLEC18A and ROSA-CLEC18A(S339R) mice are more resistant to H5N1 infection with higher survival rates than WT littermates (CLEC18A(S339R) > CLEC18A > WT) These observations suggest that CLEC18A and CLEC18A(S339R) act as TLR3 co-receptors in the endosome, and may contribute to the differential immune responses to TLR3-mediated signaling between human and mouse
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