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

Human β-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 naïve macrophages. Finally, we demonstrate that the ability of HBD3 to limit macrophage classical activation requires IL-4Rα. 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. ![Figure][1] SYNOPSIS The anti-microbial host-defence peptide, Human β-defensin 3 (HBD3), is shown here to modulate the inflammatory response to classical activation by promoting alternative activation through IL-4Rα, to enable a state conducive for repair and resolution. ### Competing Interest Statement The authors have declared no competing interest. [1]: pending:yes