Classical macrophage polarisation is limited by human β-defensin 3 via an autocrine IL-4 dependent process.

Human {beta}-defensin 3 (HBD3), is an anti-microbial host-defence peptide, that can rapidly enter macrophages to modulate TLR4 responses to lipopolysaccharide. However, the molecular mechanisms by which HBD3 exerts this anti-inflammatory influence remain unclear. Here, we show mice deleted for the orthologue of HBD3 have an increased acute lipopolysaccharide response in vivo. Furthermore, we found that HBD3 limited the response of macrophages to classical activation, and contemporaneously drove expression of IL-4. An increase in markers of alternative activation, and a change in metabolic flux was also observed. Consistent with these results, HBD3 enhanced the IL-4 mediated polarisation of naive macrophages. Finally, we demonstrate that the ability of HBD3 to limit macrophage classical activation requires IL-4R. These data reveal a previously unrecognised role for HBD3 in influencing the polarisation state of macrophages to enable a state conducive for repair and resolution. SYNOPSIS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/442606v2_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@f81c9aorg.highwire.dtl.DTLVardef@11dca23org.highwire.dtl.DTLVardef@c1e241org.highwire.dtl.DTLVardef@ed46ed_HPS_FORMAT_FIGEXP M_FIG C_FIG The anti-microbial host-defence peptide, Human {beta}-defensin 3 (HBD3), is shown here to modulate the inflammatory response to classical activation by promoting alternative activation through IL-4R, to enable a state conducive for repair and resolution. O_LIKnockout mice for the orthologous gene for HBD3, demonstrate increased acute lipopolysaccharide inflammatory response. C_LIO_LIHBD3 limited the classical activation of macrophages polarised with LPS/IFN{gamma} and drove expression of IL-4. Cells also displayed increase in alternative activation markers and promotion of oxidative phosphorylation. C_LIO_LIHBD3 enhanced the IL-4-mediated activation of naive macrophages. C_LIO_LIThe ability of HBD3 to limit macrophage classical activation and contemporaneously promote alternative activation required IL-4R. C_LI