Platelet-derived β2M regulates monocyte inflammatory responses
Zachary T. Hilt, … , Michael R. Elliott, Craig N. Morrell
Zachary T. Hilt, … , Michael R. Elliott, Craig N. Morrell
Published March 7, 2019; First published January 31, 2019
Citation Information: JCI Insight. 2019;4(5):e122943. https://doi.org/10.1172/jci.insight.122943.
View: Text | PDF
Research Article Vascular biology

Platelet-derived β2M regulates monocyte inflammatory responses

Abstract

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 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 β2M is a mediator of monocyte proinflammatory differentiation through noncanonical TGFβ receptor signaling. Circulating monocytes from mice lacking β2M only in platelets (Plt-β2M–/–) had a more proreparative monocyte phenotype, in part dependent on increased platelet-derived TGFβ signaling in the absence of β2M. Using a mouse myocardial infarction (MI) model, Plt-β2M–/– 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 β2M and that platelet-derived 2M and TGFβ have opposing roles in monocyte differentiation that may be important in tissue injury responses.

Authors

Zachary T. Hilt, Daphne N. Pariser, Sara K. Ture, Amy Mohan, Pearl Quijada, Akua A. Asante, Scott J. Cameron, Julie A. Sterling, Alyssa R. Merkel, Andrew L. Johanson, Jermaine L. Jenkins, Eric M. Small, Kathleen E. McGrath, James Palis, Michael R. Elliott, Craig N. Morrell

×

Figure 1

Platelets are a major source of plasma β2M.

Options: View larger image (or click on image) Download as PowerPoint
Platelets are a major source of plasma β2M. (A) Activated platelets rele...
(A) Activated platelets release β2M. Mouse platelets were isolated and treated with control buffer, ADP (10 μM), or thrombin (1 U/ml). β2M release was measured by ELISA (n = 4, *P < 0.05, **P < 0.01, 1-way ANOVA with Bonferroni correction). (B) Platelets, but not WBC, from Plt-β2M–/– mice lack MHC I surface expression. Anti–MHC I or control IgG was incubated with circulating platelets or CD45+ cells (insert) from WT and Plt-β2M–/–. MHC I was quantified by flow cytometry (n = 3, **P < 0.01, 1-way ANOVA with Bonferroni correction). (C) Platelets from WT and Plt-β2M–/– mice had similar activation and aggregation. Washed WT and Plt-β2M–/– platelets were stimulated with ADP, and surface P-selectin was measured. Platelets were also labeled with APC or PE antibodies, thrombin stimulated and platelet aggregates determined as double-positive cells by flow cytometry (n = 4 for both panels, 1-way ANOVA with Bonferroni correction). (D) Platelets are a major source of plasma β2M. Concentration of plasma β2M in 10-week-old WT and Plt-β2M–/– mice was determined by ELISA (n = 5, WT; n = 6, Plt-β2M–/–; *P < 0.05 vs. WT, unpaired 2-tailed t test with Welch’s correction).