Platelet-derived β2M regulates monocyte inflammatory responses

beta-2 Microglobulin (beta 2M) is a molecular chaperone for the major histocompatibility class I (MHC I) complex, hemochromatosis factor protein (HFE), and the neonatal Fc receptor (FcRn), but beta 2M may also have less understood chaperone-independent functions. Elevated plasma beta 2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. beta 2M mRNA is present in platelets at very high levels, and beta 2M is part of the activated platelet releasate. In addition to their more well-studied thrombotic functions, platelets are important immune regulatory cells that release inflammatory molecules and contribute to leukocyte trafficking, activation, and differentiation. We have now found that platelet-derived beta 2M is a mediator of monocyte proinflammatory differentiation through noncanonical TGF beta receptor signaling. Circulating monocytes from mice lacking beta 2M only in platelets (Plt-beta 2M(-/-)) had a more proreparative monocyte phenotype, in part dependent on increased platelet-derived TGF beta signaling in the absence of beta 2M. Using a mouse myocardial infarction (MI) model, Plt-beta 2M(-/-) mice had limited post-MI proinflammatory monocyte responses and, instead, demonstrated early proreparative monocyte differentiation, profibrotic myofibroblast responses, and a rapid decline in heart function compared with WT mice. These data demonstrate a potentially novel chaperone-independent, monocyte phenotype-regulatory function for platelet beta 2M and that platelet-derived 2M and TGF beta have opposing roles in monocyte differentiation that may be important in tissue injury responses.