Multinucleated giant cells (MGCs) form as a result of monocyte or macrophage cell fusion during processes such as infections or autoimmune disorders. However, the molecular basis of MGC formation is poorly understood. In their work, Christopher McCulloch and co-workers (Brooks et al., 2020) search for novel regulators of macrophage fusion using a tandem mass tag mass spectrometry approach in primary mouse bone marrow monocytes. Unexpectedly, they find that the C-type lectin CD301 is upregulated upon IL-4-induced MGC formation. In mouse macrophages, CD301 predominantly localises to the plasma membrane. By pre-treating these cells with antibodies against the CD301 isotypes Mgl1 and Mgl2, the authors show that CD301 inhibition impairs IL-4-induced macrophage fusion and the formation of MGCs. Similarly, the number of cell fusion events was diminished in macrophages that carried either an Mgl2 single knockout or Mgl1/2 double knockout. The authors recapitulate these findings in human macrophages, in which cell fusion mediated by IL-4-induced expression of CD301 can be reduced by interfering with the ability of ligands to bind and activate membranous CD301. Lastly, the authors show that CD301 is expressed in biopsies of two human inflammatory lesions. Collectively, these findings establish CD301 as a novel, conserved factor that promotes macrophage cell fusion to form MGCs, thus making it a potential candidate to help diagnose and treat MGC-containing lesions.

• © 2020. Published by The Company of Biologists Ltd