The contribution of ion channels to shaping macrophage behaviour

Abstract

The expanding roles of macrophages in physiological and pathophysiological mechanisms now include normal tissue homeostasis, tissue repair and regeneration, including neuronal tissue; initiation, progression, and resolution of the inflammatory response and a diverse array of anti-microbial activities. Two hallmarks of macrophage activity which appear to be fundamental to their diverse cellular functionalities are cellular plasticity and phenotypic heterogeneity. Macrophage plasticity allows these cells to take on a broad spectrum of differing cellular phenotypes in response to local and possibly previous encountered environmental signals. Cellular plasticity also contributes to tissue- and stimulus-dependent macrophage heterogeneity, which manifests itself as different macrophage phenotypes being found at different tissue locations and/or after different cell stimuli. Together, plasticity and heterogeneity align macrophage phenotypes to their required local cellular functions and prevent inappropriate activation of the cell, which could lead to pathology. To execute the appropriate function, which must be regulated at the qualitative, quantitative, spatial and temporal levels, macrophages constantly monitor intracellular and extracellular parameters to initiate and control the appropriate cell signaling cascades. The sensors and signaling mechanisms which control macrophages are the focus of a considerable amount of research. Ion channels regulate the flow of ions between cellular membranes and are critical to cell signaling mechanisms in a variety of cellular functions. It is therefore surprising that the role of ion channels in the macrophage biology has been relatively overlooked. In this review we provide a summary of ion channel research in macrophages. We begin by giving a narrative-based explanation of the membrane potential and its importance in cell biology. We then report on research implicating different ion channel families in macrophage functions. Finally, we highlight some areas of ion channel research in macrophages which need to be addressed, future possible developments in this field and therapeutic potential.

Single-cell RNA sequencing analysis of vestibular schwannoma reveals functionally distinct macrophage subsets

“…Interestingly, Cluster 1 involved predominantly potassium and voltage gated channels pathway. Potassium channels and other voltage gated channels have recently been shown to have important roles in macrophage function such as iNOS production, phagocytosis and intracellular signalling [ 67 ]. Transcriptional activity (DoroThea) promoting tumourigenesis and regulation of inflammation was also different between the three clusters of macrophages suggesting that they could influence tumour growth and tumoural inflammation.…”

Piezo1 stretch-activated channel activity differs between bone marrow-derived and cardiac tissue-resident macrophages

“…This is in line with previous studies reporting the expression and activity of several members of the TRP family (including TRPM2/4/7/8, TRPC1/3/6 [canonical], TRPV1/2/4, TRPA1 [ankyrin], TRPM1/2/3 [mucolipins], TRPP2) in myeloid cells. These channels have been implicated in the control of cell proliferation and survival, polarisation, mobility, phagocytosis, intercellular communication, and inflammatory responses (as reviewed in (Santoni, Morelli et al 2018, Selezneva, Gibb et al 2022)).…”

The role of macrophage ion channels in the progression of atherosclerosis

“…Ion channels are transmembrane proteins that enable the passage of ions across cell membranes and regulate physiological processes (15)(16)(17)(18)(19)(20)(21)(22)(23). Recent studies have shown ion channels regulate macrophage function (3,4). Several ion channels in macrophages are implicated in immune responses and inflammatory diseases.…”

“…Several ion channels in macrophages are implicated in immune responses and inflammatory diseases. The macrophage ion channels include potassium channel, transient receptor potential (TRP) channel, calcium channel, mechanosensitive Piezo channel, chloride channel, and proton channel (3)(4)(5).…”

“…Ion channels, transmembrane proteins that allow the flow of ions across cell membranes, are emerging as important regulators of macrophage function ( 3 , 4 ). Recent studies have revealed diverse roles of ion channels in macrophages and their implications in immune responses and inflammatory diseases, including atherosclerosis ( 5 ).…”