Ablation of Cbl-b and c-Cbl in macrophages causes severe spontaneous lung inflammation via enhancing the M-CSFR signaling pathway

The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in macrophages remains unclear. We show that macrophage-specific deficiency of Cbl-b and c-Cbl (Cbls) causes mice to die prematurely from spontaneous macrophage massive invasive lung inflammation. Mechanically, we identify that Cbls functions upstream of AKT and Erk to mediate the ubiquitination and degradation of M-CSFR. upon M-CSF stimulation, M-CSF binds to M-CSFR to activates downstream PI3K-AKT and Erk signaling pathways. At the same time, autophosphorylation of tyrosine at position 559 on M-CSFR receptor can promote receptor recruitment and phosphorylation of Cbls, and phosphorylated activated Cbls can target lysine at position 791 of M-CSFR for K63 linked-polyubiquitination modification. Eventually, the receptor is internalized and degraded through the lysosomal pathway, preventing the signaling pathway from being over-activated. Thus, Cbls deficiency in macrophages promotes M-CSF-induced activation of M-CSFR, AKT and Erk, which causes the accumulation of systemic macrophages due to increased cell proliferation and decreased apoptosis. Together, these data demonstrate that Cbl-b and c-Cbl play critical roles in the regulation of macrophage homeostasis by inhibiting M-CSFR-mediated AKT and Erk activation.