Interleukin-4-induced β-catenin regulates the conversion of macrophages to multinucleated giant cells

The cytokine interleukin-4 (IL-4) exerts pleiotropic effects on macrophages as it plays a key role in the immune response to infectious agents, allergens, and vaccines. Macrophages exposed to IL-4 drastically change their gene expression and metabolic state to adjust to new functional requirements. IL-4 also induces macrophages to fuse together and form multinucleated giant cells (MGCs). MGC formation is associated with chronic inflammation resulting from persistence of pathogenic microorganisms or foreign materials in tissues. Very little is known, however, about the mechanisms regulating IL-4-induced macrophage-to-MGC conversion. We observed a dramatic increase in β-catenin protein but not mRNA amount in mouse macrophages following exposure to IL-4. To investigate the role of β-catenin in macrophages, we generated mice with a myeloid cell-specific deletion of the β-catenin gene. Ablation of β-catenin expression did not affect the viability of macrophages or impair expression of known IL-4-inducible genes. Intriguingly, β-catenin-deficient macrophages incubated with IL-4 formed MGCs with markedly greater efficiency than wild-type macrophages. Similar increases in multinucleated cell formation were detected in the peritoneal cavity of myeloid cell-specific β-catenin knockout mice injected with chitin, which is known to induce endogenous IL-4 production. Our findings reveal β-catenin as a novel regulator of macrophage responses to IL-4, and suggest that therapeutic modulation of its expression or function may help enhance the effectiveness or ameliorate the pathology of IL-4-driven immune responses.

► IL-4 induces β-catenin protein but not mRNA in mouse macrophages.
► Macrophages lacking β-catenin form MGCs with greater efficiency after IL-4 exposure.
► MGC formation in vivo is regulated by myeloid cell-specific β-catenin function.