Myc binding protein 2 suppresses M2-like phenotypes in macrophages during zymosan-induced inflammation in mice

MYCBP2 is an E3 ubiquitin ligase, which is well characterized as a key element in the inhibition of neuronal growth, synapse formation and synaptic strength by regulating several signaling pathways. Although MYCBP2 was suspected to be expressed also in immune cells, to date nothing is known about its role in inflammation. We used Multi-epitope ligand cartography (MELC), a method for multiple sequential immunohistology, to show that MYCBP2 is strongly expressed in monocyte-derived macrophages during zymosan-induced inflammation. We generated a myeloid-specific knockout mouse and found that loss of MYCBP2 in myeloid cells reduced nociceptive (painful) behavior during the resolution phase (1-3 days after zymosan injection). Quantitative MELC analyses and flow cytometric analysis showed an increased number of CD206-expressing macrophages in the inflamed paw tissue. Fittingly, CD206 and arginase 1 expression was upregulated in MYCBP2-deficient bone marrow-derived macrophages after polarization with IL10 or IL4. The regulation of protein expression in these macrophages by MYCBP2 varied depending on the polarization signal. The increased IL10-induced CD206 expression in MYCBP2-deficient macrophages was mediated by p38 MAPK, while IL4-induced CD206 expression in MYCBP2-deficient macrophages was mediated by protein kinase A.