Platelet-derived ?2M regulates monocyte inflammatory responses.

ABSTRACT: ?-2 Microglobulin (?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 ?2M may also have less understood chaperone-independent functions. Elevated plasma ?2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. ?2M mRNA is present in platelets at very high levels, and ?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 ?2M is a mediator of monocyte proinflammatory differentiation through noncanonical TGF? receptor signaling. Circulating monocytes from mice lacking ?2M only in platelets (Plt-?2M-/-) had a more proreparative monocyte phenotype, in part dependent on increased platelet-derived TGF? signaling in the absence of ?2M. Using a mouse myocardial infarction (MI) model, Plt-?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 ?2M and that platelet-derived 2M and TGF? have opposing roles in monocyte differentiation that may be important in tissue injury responses.

SUBMITTER: Hilt ZT 

PROVIDER: S-EPMC6483513 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature