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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 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

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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 6

Platelet β2M regulates circulating monocyte differentiation.

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Platelet β2M regulates circulating monocyte differentiation.
(A) Circula...
(A) Circulating monocytes were isolated from WT and Plt-β2M–/– mice, and proinflammatory and proreparative monocyte gene markers were quantified by qPCR. Plt-β2M–/– mouse monocytes had proreparative monocyte gene expression (all panels, n = 3; *P < 0.05, unpaired 2-tailed t test with Welch’s correction). (B and C) Monocytes from Plt-β2M–/– mice differentiate to proreparative, fibroblast activating, macrophages in vitro. Peripheral blood monocytes from WT and Plt-β2M–/– mice were coincubated with cardiac fibroblasts for 72 hours and macrophage differentiation (B) and fibroblast activation (C) were determined by qPCR, and IL-10 secretion determined by ELISA. Plt-β2M–/––derived monocytes had increased proreparative differentiation and IL-10 secretion and induced more fibroblast activation compared with WT mouse monocytes (B and C, n = 4; *P < 0.05, **P < 0.01 vs. WT, unpaired 2-tailed t test with Welch’s correction).

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