# Ion Flux Regulation of Macrophage Plasticity in Lung Injury and Repair

> **NIH NIH P01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $425,505

## Abstract

PROJECT SUMMARY/ABSTRACT
Macrophages (Mφ) are essential for the innate immune function of lungs. The ability of macrophages to
integrate signals from microbes and the tissue niche and to polarize can either promote or resolve
inflammatory lung injury. Project 1 shows a fundamental role of the extracellular ATP (e[ATP]) activated- and
[Ca2+]in-sensitive cooperation between the purinergic receptor P2RX7 (Purinergic Receptor 2 subtype X7) and
potassium (K+) channel TWIK2 (Two-pore domain Weak Inwardly rectifying K+ channel 2) that is essential for
determining the macrophage phenotype. We show that e[ATP], the canonical P2RX7 ligand, governs Mφ
polarization through controlling [Ca2+]in and that activation of the TWIK2 K+ efflux channel induces the transition
to the pro-inflammatory state. We also observed that the TWIK2 response was itself dependent on the
activation of P2RX7 by e[ATP] and resultant Ca2+ influx. Thus, Project 1, we will investigate the interactions
between Ca2+ influx mediated by P2RX7 and its tuning of K+ efflux mediated by TWIK2, which we hypothesize
determines the transition to either pro-inflammatory Mφ (Inf-Mφ) or reparative Mφ (Rep-Mφ) fate via activation
of distinct downstream signaling pathways. This hypothesis will be tested by addressing the following Specific
Aims. Aim 1 will define respective mechanisms of P2RX7 and TWIK2 activation in mediating the shift in lung
macrophage polarity. Aim 2 will define the signaling pathways downstream of Mφ ion channels that promote
and resolve inflammatory lung injury. We posit that by identifying P2RX7 and TWIK2 activation and signaling
mechanisms responsible for macrophage phenotype switching, and by testing the role of P2RX7 in
coordinating the function of TWIK2 in the initial inflammatory response followed subsequent anti-inflammatory
response in Project 1, it will be possible to develop strategies to more effectively resolve inflammatory lung
injury and to make lung’s tolerance to injury through controlling macrophage polarization enhancing bacterial
killing function of MФ.

## Key facts

- **NIH application ID:** 10701929
- **Project number:** 5P01HL151327-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Asrar B. Malik
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $425,505
- **Award type:** 5
- **Project period:** 2021-09-20 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10701929

## Citation

> US National Institutes of Health, RePORTER application 10701929, Ion Flux Regulation of Macrophage Plasticity in Lung Injury and Repair (5P01HL151327-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10701929. Licensed CC0.

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