Ion Flux Regulation of Macrophage Plasticity in Lung Injury and Repair

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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.