# RSV-induced M2 macrophage differentiation: role of TLR4/PPARg/RXR signaling axis (80)

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $190,063

## Abstract

PROJECT SUMMARY/ABSTRACT
 Monocytes and macrophages (Mf) sense the presence of pathogens, tissue damage, and host-derived
mediators in their environment and respond by differentiating into distinct functional phenotypes that mediate
host innate immune responses. For example, “classically activated” (M1) macrophages are highly microbicidal,
yet their production of inflammatory mediators may also damage host tissue. At the other end of a functional
spectrum, “alternatively activated” (M2) macrophages, induced by IL-4 and IL-13, mediate “wound healing”
through elimination of damaged tissue and other anti-inflammatory mechanisms.
 The Blanco and Vogel laboratories have worked closely together to study the host response to Respiratory
Syncytial Virus (RSV), the most significant cause of severe lower respiratory tract infection in infants, the elderly,
and immunosuppressed individuals. In wild-type (WT) mice, RSV infection elicits an early, transient M1 Mf re-
sponse in the lung that is followed by a more sustained period of M2 Mf predominance and resolution of inflam-
matory lung pathology. We reported that IL-4Ra-/- mice, that fail to respond to RSV infection with the development
of M2 Mf, exhibit greatly enhanced lung pathology that can be overcome by adoptive transfer of WT Mf that
differentiate into M2 Mf upon RSV infection. Importantly, RSV-induced TLR4 signaling was shown to be a pre-
requisite for induction of the transcription factor peroxisome proliferator-activated receptor gamma (PPARg).
PPARg forms heterodimers with retinoid X receptor (RXR) that bind to M2 Mf gene promoters and activate tran-
scription of M2 Mf genes. Our primary objective in this R21 application is to define in greater detail mechanisms
governing the TLR4-induced PPARg/RXR signaling axis and the consequences of M2 Mf in the resolution of
RSV infection. The overarching hypothesis to be tested is that the balance of M1 and M2 Mf during RSV infection
dictates the extent of RSV disease. By comparing the responses of WT mice and mice with PPARg-deficient Mf
in vivo and in vitro, we will determine the role of TLR4-induced PPARg/RXR axis in the regulation of M2 Mf
development in RSV (Specific Aim 1). In Specific Aim 2, Targeting the TLR4-induced PPARg/RXR signal-
ing axis in the cotton rat model of RSV, we will extend our findings using cotton rats, the gold standard for
development of RSV therapies, to test the hypothesis that therapeutic administration of PPARg and RXR agonists
to infected cotton rats will result in synergistic M2 Mf differentiation that, in turn, will mitigate inflammatory lung
damage normally caused by RSV infection. These two aims are based on our strong published and preliminary
data, and support the concept that the balance between M1 Mf-mediated inflammatory lung damage and
PPARg/RXR-driven transcription of M2 Mf genes, leading to tissue repair, dictates the ultimate outcome. At the
conclusion of these exploratory studies, key processes that lead to cha...

## Key facts

- **NIH application ID:** 10418803
- **Project number:** 5R21AI163543-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** JORGE C BLANCO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $190,063
- **Award type:** 5
- **Project period:** 2021-06-07 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418803

## Citation

> US National Institutes of Health, RePORTER application 10418803, RSV-induced M2 macrophage differentiation: role of TLR4/PPARg/RXR signaling axis (80) (5R21AI163543-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10418803. Licensed CC0.

---

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