# Macrophage-specific Pair Immunoglobulin-like Type 2 Receptor beta (PILRB) regulation of Pulmonary Hypertension

> **NIH NIH R03** · UNIVERSITY OF COLORADO DENVER · 2021 · $77,750

## Abstract

ABSTRACT
Pulmonary hypertension (PH), arising from primary pulmonary vascular disease or secondary to many other
conditions, is associated with high morbidity and mortality. Despite recent therapeutic advancements, PH
hospitalization and mortality continue to rise. Development of effective therapy is needed but is limited by a
fundamental knowledge gap in our understanding of cells and mechanisms that regulate pulmonary vascular
remodeling underlying PH development. Macrophage (MØ) accumulation is observed in animal models and
human PH suggesting a role for monocytes/MØs in regulating PH pathogenesis, My K08 award centered on
defining the contribution of monocytes/MØs to PH pathogenesis. I demonstrated that non-classical monocytes
(NcMos) sense hypoxia, through hypoxia inducible factor-1α (HIF1α), and differentiate into pro-vascular
remodeling interstitial MØs (IMØs) that promote PH development. Effective targeting of these disease promoting
cells to alleviate disease will require an understanding of mechanisms by which they regulate vascular
remodeling. I identified paired immunoglobulin-like type 2 receptor beta (PILRβ) as a candidate NcMo-derived
IMØ-specific disease mediator. We hypothesize that, in response to hypoxia and activation of HIF1α: 1) PILRβ
expression in infiltrating IMØs is increased and 2) PILRβ engages its receptor, CD99, on vascular structural cells
(i.e. endothelial cells, vascular smooth muscle cells, and fibroblasts) to increase the production of cytokines (e.g.
TNF, IL-1β, and IL-6) that promote pulmonary vascular remodeling and PH development. Our preliminary studies
show that gene expression of PILRβ is decreased in Hif1α-deficient IMØs. This decrease is associated with
lower expression of pro-vascular remodeling cytokines (i.e. TNF, IL-1, and IL6), as well as reduced severity of
vascular remodeling and PH. These findings suggest that PILRβ is a NcMo/IMØ-specific mediator that modulates
PH pathogenesis. Utilizing transgenic animal and human PAH lung tissue collection developed during my K08
award, we propose the following specific aims: Aim 1. To determine the expression patterns of PILRβ
receptor complex and its regulation by HIF1α in a murine model and human PH. NcMo-specific Hif1α
knockout mice will be examined in a model of hypoxia-induced PH to define PILRβ expression pattern over the
course of PH development. PILRβ expression in human PAH lung will also be examined. Aim 2. To determine
the cells that express CD99, a ligand for PILRβ, and ligand expression in response to chronic hypoxia
and in human PH. CD99 expression will be examined over the course of PH development in hypoxia-induced
PH and human PAH lung explants. Aim 3. To determine cytokine response during PH development that is
modulated by infiltrating IMØs to promote vascular remodeling. Cytokine responses over the course of PH
development will be examined in NcMo-specific Hif1α knockout mice and in human PAH lung explants. The
proposed studies will provid...

## Key facts

- **NIH application ID:** 10281899
- **Project number:** 1R03HL158640-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Yen-Rei Andrea Yu
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $77,750
- **Award type:** 1
- **Project period:** 2021-09-21 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10281899

## Citation

> US National Institutes of Health, RePORTER application 10281899, Macrophage-specific Pair Immunoglobulin-like Type 2 Receptor beta (PILRB) regulation of Pulmonary Hypertension (1R03HL158640-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10281899. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*