BCAP mediates canonical M2 macrophage differentiation and promotes tumor progression 2506

Abstract Description Upon microbial sensing, macrophages adopt a pro-inflammatory M1 state that is critical for eliminating the pathogen. Following clearance of the insult, macrophages transition into an anti-inflammatory M2 state and promote repair to return the damaged tissue to homeostasis. Interestingly, several other cell extrinsic signals such as IL-4 and IL-33 can instruct macrophages to adopt a M2 reparative state. We previously identified B-cell adaptor for PI3K (BCAP), acting downstream of TLRs, as a key player in facilitating the transition of macrophages from a pro-inflammatory to a reparative state. Whether BCAP also plays a role in macrophage differentiation upon sensing other extrinsic signals remains unclear. Here, we found that, following IL-4 and IL-33 stimulation, BCAP deficient macrophages exhibited a defective M2 gene program as revealed by reduced expression of Arg1, Retnla, and Mgl2. Upon IL-4 stimulation, adaptor proteins IRS2 and Grb2 are recruited to the IL-4 receptor to activate the PI3K-Akt pathway. Our data reveal that BCAP interacts with Grb2 and IRS2 to facilitate PI3K activation and BCAP deficient macrophages exhibit defective PI3K-Akt activation downstream of IL-4R. Importantly, growth of implanted tumors in BCAP deficient mice as well as mice lacking BCAP specifically in macrophages was significantly compromised. Our findings suggest BCAP to be a critical node for detecting several cell extrinsic signals that directly drive canonical M2 differentiation. Funding Sources Supported by Cincinnati Childrens Research Foundation Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)