# Platelet Derived Beta-2 Microglobulin Regulates Monocyte Homeostasis

> **NIH NIH F31** · UNIVERSITY OF ROCHESTER · 2020 · $1,055

## Abstract

Project Summary
Platelets are the cellular mediators of thrombosis, but they also have central roles in immune responses.
Stimulated platelets release many soluble immune mediators that recruit and activate white blood cells. Beta-2
microglobulin (β2M) is a chaperone molecule essential for MHCI trafficking and stability. Platelets contain
abundant β2M that is released upon activation into the extracellular environment. Elevated plasma β2M is
associated with increased risk for inflammatory diseases, including cardiac events, and previous reports
suggested it has direct signaling effects on monocytes. Through preliminary studies we have shown that β2M
directly promotes a pro-inflammatory response in monocytes. We have generated unique platelet specific
β2M-/- (Plt-β2M-/-) mice that we will use with a MI model to determine the mechanisms of β2M regulated
monocyte responses and their effect on inflammation and fibrosis. Using this novel mouse model, we have
discovered that platelets are the major source of plasma β2M and that it is significantly elevated post-
myocardial infarction (MI). Work from our lab has shown that platelet-derived β2M is critical to a pro-
inflammatory (Ly6CHi) monocyte response post-MI. This lead us to hypothesize that platelet derived β2M is a
novel regulator of monocyte response to MI. To pursue this hypothesis, I propose the following Aims: 1) To
demonstrate mechanisms of platelet mediated monocyte inflammatory phenotype, 2) To demonstrate
how platelet-derived β2M mediates monocyte responses and outcomes in an ischemic myocardial
injury model. We will perform studies using primary mouse and human monocytes as well as a human
monocytic cell-line (THP-1) to demonstrate the signaling mechanisms of β2M related monocyte polarization.
Monocyte phenotype will be characterized by surface markers using flow cytometry and cytokines using
ELISA. We will determine the mechanism of β2M-induced monocyte activation through use of surface plasmon
resonance and receptor and signal transduction inhibitors, confirmed by immunoblot. Heart function and MI
responses in our WT and Plt-β2M-/- mice will be analyzed using echocardiogram and histology. Plasma will be
collected to determine the cytokine profile of our mouse models. Hearts will be collected for qRT-PCR and
single cell isolation to phenotype the macrophages and fibrotic responses to MI. These data will define novel
non-chaperone, direct inflammatory roles for β2M in monocyte and subsequent macrophage responses to MI.

## Key facts

- **NIH application ID:** 9960308
- **Project number:** 5F31HL145922-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Zachary T Hilt
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,055
- **Award type:** 5
- **Project period:** 2019-04-01 → 2020-04-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960308

## Citation

> US National Institutes of Health, RePORTER application 9960308, Platelet Derived Beta-2 Microglobulin Regulates Monocyte Homeostasis (5F31HL145922-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9960308. Licensed CC0.

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