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.
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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

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Figure 7

Platelet-derived β2M mediates monocyte inflammatory responses to myocardial infarction.

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Platelet-derived β2M mediates monocyte inflammatory responses to myocard...
(A) Plasma β2M is elevated in humans after MI. Plasma was isolated from healthy subjects and confirmed MI patients. β2M was measured by ELISA (n = 22, control; n = 55, MI; *P < 0.05 vs. control, unpaired 2-tailed t test with Welch’s correction). (B) WT, but not Plt-β2M–/–, mice had increased post-MI plasma β2M. β2M measured before and 1 day after MI by ELISA (n = 5; *P < 0.05 vs. Plt-β2M–/–, 1-way ANOVA with Bonferroni correction). (C) WT mice had increased circulating Ly6Chi monocytes after MI, but Plt-β2M–/– mice had no change from day 0 (n = 3, WT at 0 and 2 days, and Plt-β2M–/– at 0, 2, and 3 days; n = 4, WT at 3 and 18 days, and Plt-β2M–/– at 18 days; n = 5, Plt-β2M–/– at 7 days; n = 6, WT at 7 days; *P < 0.05, **P < 0.01, 1-way ANOVA with Bonferroni correction). (D) Plt-β2M–/– mice had a rapid post-MI decline in heart function compared with WT mice (n = 5, *P < 0.05 vs. Plt-β2M–/–, unpaired 2-tailed t test with Welch’s correction). (E) WT and Plt-β2M–/– mice had similar post-MI monocyte lineage infiltrates (CD68+), but monocytes are associated with areas of ECM deposition (trichrome) in Plt-β2M–/– mice. Representative images 20× images, from day 15 after MI. (F) Fibrosis quantification (n = 3, control; n = 4, day 15 after MI; *P < 0.05, 1-way ANOVA with Bonferroni correction).