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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

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Platelet-derived β2M regulates monocyte inflammatory responses.

Hilt Zachary T ZT Pariser Daphne N DN Ture Sara K SK Mohan Amy A Quijada Pearl P Asante Akua A AA Cameron Scott J SJ Sterling Julie A JA Merkel Alyssa R AR Johanson Andrew L AL Jenkins Jermaine L JL Small Eric M EM McGrath Kathleen E KE Palis James J Elliott Michael R MR Morrell Craig N CN

JCI insight 20190307 5

β-2 Microglobulin (β2M) is a molecular chaperone for the major histocompatibility class I (MHC I) complex, hemochromatosis factor protein (HFE), and the neonatal Fc receptor (FcRn), but β2M may also have less understood chaperone-independent functions. Elevated plasma β2M has a direct role in neurocognitive decline and is a risk factor for adverse cardiovascular events. β2M mRNA is present in platelets at very high levels, and β2M is part of the activated platelet releasate. In addition to their ...[more]

PMID: 30702442

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Project description:Platelets store and release CXCL12 (SDF-1), which governs differentiation of hematopoietic progenitors into either endothelial or macrophage-foam cells. CXCL12 ligates CXCR4 and CXCR7 and regulates monocyte/macrophage functions. This study deciphers the relative contribution of CXCR4-CXCR7 in mediating the effects of platelet-derived CXCL12 on monocyte function, survival, and differentiation. CXCL12 and macrophage migration inhibitory factor (MIF) that ligate CXCR4-CXCR7 induced a dynamic bidirectional trafficking of the receptors, causing CXCR4 internalization and CXCR7 externalization during chemotaxis, thereby influencing relative receptor availability, unlike MCP-1. In vivo we found enhanced accumulation of platelets and platelet-macrophage co-aggregates in peritoneal fluid following induction of peritonitis in mice. The relative surface expression of CXCL12, CXCR4, and CXCR7 among infiltrated monocytes was also enhanced as compared with peripheral blood. Platelet-derived CXCL12 from collagen-adherent platelets and recombinant CXCL12 induced monocyte chemotaxis specifically through CXCR4 engagement. Adhesion of monocytes to immobilized CXCL12 and CXCL12-enriched activated platelet surface under static and dynamic arterial flow conditions were mediated primarily through CXCR7 and were counter-regulated by neutralizing platelet-derived CXCL12. Monocytes and culture-derived-M1-M2 macrophages phagocytosed platelets, with the phagocytic potential of culture-derived-M1 macrophages higher than M2 involving CXCR4-CXCR7 participation. CXCR7 was the primary receptor in promoting monocyte survival as exerted by platelet-derived CXCL12 against BH3-mimetic induced apoptosis (phosphatidylserine exposure, caspase-3 activation, loss of mitochondrial transmembrane potential). In co-culture experiments with platelets, monocytes predominantly differentiated into CD163(+) macrophages, which was attenuated upon CXCL12 neutralization and CXCR4/CXCR7 blocking antibodies. Moreover, OxLDL uptake by platelets induced platelet apoptosis, like other platelet agonists TRAP and collagen-related peptide (CRP). CXCL12 facilitated phagocytosis of apoptotic platelets by monocytes and M1-M2 macrophages, also promoted their differentiation into foam cells via CXCR4 and CXCR7. Thus, platelet-derived CXCL12 could regulate monocyte-macrophage functions through differential engagement of CXCR4 and CXCR7, indicating an important role in inflammation at site of platelet accumulation.

Dataset Information

Platelet-derived ?2M regulates monocyte inflammatory responses.

Publications

Platelet-derived β2M regulates monocyte inflammatory responses.

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