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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 4

β2M proinflammatory phenotype signaling is through noncanonical TGFβ receptor signaling.

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β2M proinflammatory phenotype signaling is through noncanonical TGFβ rec...
(A) Inhibition of TGFβR signaling ameliorated β2M-induced monocyte activation. Mouse monocytes were incubated with control buffer, β2M, or β2M and a TGFβR1 kinase inhibitor (SB431542). KC production was determined 48 hours later (n = 4; **P < 0.01, 1-way ANOVA with Bonferroni correction). (B) β2M binds to TGFβR1 and TGFβR2. Fc-TGFβR1 or Fc-TGFβR2 were immobilized on a sensor chip, and β2M, TGFβ1, or TGFβ3 binding was determined by SPR. (C and D) WT and TGFβR2–/– monocytes were incubated with control buffer or β2M. (C) β2M induced WT, but not TGFβR–/– monocyte, Ly6Chi phenotype. (D) Quantification of C (n = 4; *P < 0.05, 1-way ANOVA with Bonferroni correction).

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