Proteolytic shedding of integrin beta 2 promotes macrophage resolution of inflammation

While the contribution of integrin beta 2 to leukocyte recruitment during inflammation is well established, the potential importance of soluble integrin beta 2 heterodimers in physiological fluids to the inflammatory response is unknown. This study demonstrates metalloproteinase shedding of integrin beta 2 heterodimers from the surface of mouse macrophages both in vitro and in vivo. Soluble integrin beta 2 is primarily released as a heterodimeric complex with alpha M, and this complex retains its ability to bind ICAM‐1. In the thioglycollate model of peritonitis, levels of soluble integrin beta 2 are elevated at times when macrophages are exiting the peritoneum and migrating to draining lymph nodes. In vivo inhibition of metalloprotease‐mediated shedding is sufficient to prevent macrophage efflux by greater than 80% and to specifically impede the loss of macrophage integrin beta 2 from the cell surface. However, disruption of integrin beta 2 substrate interactions with antibody 2E6 can reverse 50% of the metalloprotease blockade of macrophage efflux, and thus establishes that proteolytic cleavage of macrophage integrin beta 2 during the resolution of inflammation is critical to promote macrophage exit.