The tetraspan MS4A4A modulates macrophage activation

Membrane-spanning 4A (MS4A) proteins are differentially expressed in different leukocytes subsets and evidence suggests that these proteins contribute to shape immune cell activation by working as ion channels or by modulating the signaling of other immunoreceptors. We have focused our attention on MS4A4A, which is preferentially expressed in macrophages and is overexpressed in “alternatively activated” and tumor-associated macrophages. Its expression is upregulated upon treatment with glucocorticoids (Dexamethasone, Dex). Our preliminary data showed that MS4A4A deficiency impaired the expression of Arg1 and Cd206 (anti-inflammatory genes) in BMDM while Cox2 (inflammatory gene) levels were increased, suggesting the acquisition of an inflammatory phenotype in MS4A4A-KO macrophages. A split-ubiquitin two-hybrid analysis, identified the γ signalling chain of Fcγ Receptors (FcεRI) as a new potential MS4A4A partner. To validate this, we set-up a Co-iP system and our data showed no association of MS4A4A with FcεRI in resting BMDM and in BMDM treated with glucocorticoids (Dex) or with Fc receptor ligands (Agg-IgG). Furthermore, MS4A4A does not affect Syk phosphorylation upon FcεRI engagment with Agg-IgG. Our preliminary data also showed that the expression of FcεRI protein was increased in Ms4a4a-KO BMDM compared to WT, whereas FcεRI expression was down regulated when both WT and Ms4a4a-KO BMDM were treated with Dex, although this downregulation was more pronounced in Ms4a4a-KO then WT control. Our aim is to characterize the biological function of MS4A4A and its contribution to the modulation of the signaling pathways of its partners, achieving a deeper mechanistic understanding of MS4A4A biology in macrophages and further disclose its contribution to immune responses.