Acid-Sensing Ion Channels: Expression and Function in Resident and Infiltrating Immune Cells in the Central Nervous System

Abstract

Peripheral and central immune cells are critical for fighting disease, but they can also play a pivotal role in the onset and/or progression of a variety of neurological conditions that affect the central nervous system (CNS). Tissue acidosis is often present in CNS pathologies such as multiple sclerosis, epileptic seizures, and depression, and local pH is also reduced during periods of ischemia following stroke, traumatic brain injury, and spinal cord injury. These pathological increases in extracellular acidity can activate a class of proton-gated channels known as acid-sensing ion channels (ASICs). ASICs have been primarily studied due to their ubiquitous expression throughout the nervous system, but it is less well recognized that they are also found in various types of immune cells. In this review, we explore what is currently known about the expression of ASICs in both peripheral and CNS-resident immune cells, and how channel activation during pathological tissue acidosis may lead to altered immune cell function that in turn modulates inflammatory pathology in the CNS. We identify gaps in the literature where ASICs and immune cell function has not been characterized, such as neurotrauma. Knowledge of the contribution of ASICs to immune cell function in neuropathology will be critical for determining whether the therapeutic benefits of ASIC inhibition might be due in part to an effect on immune cells.

Keywords: acid-sensing ion channel (ASIC); acidosis; central nervous system; immune cell; ion channel; neuroimmunology; neuropathology.

FIGURE 1

Schematic showing tissues in which ASICs are expressed (green boxes) and their putative role in various pathologies (orange boxes) in (A) rodents and (B) humans. Data summarized here are drawn from Supplementary Table 1, with expression sites and pathology based on studies that used antibody staining, transcriptomic data, proteomics and/or functional methods. Additional information is available in the Human Protein Atlas (www.proteinatlas.org). References supporting the putative roles of ASICs in human pathologies are as follows: ¹Brain: ASIC1a detected using RT-PCR and Western blot; acidosis-mediated damage to cultured human brain neurons rescued by ASIC1a inhibition with PcTx1 (Li et al., 2010). Significant association between ASIC1a SNPs, amygdala volume, and panic disorder in humans (Smoller et al., 2014). Elevated levels of ASIC1a (Yang et al., 2016) and ASIC3 (Cao et al., 2016) in brains of patients with temporal lobe epilepsy shown using immunostaining and Western blot. ASIC expression in CNS; treatment with amiloride alleviated patient symptoms of MS (Arun et al., 2013). ASIC1 and ASIC3 found in glioblastoma stem cell lines using RT-PCR and Western blot; microarray data revealed that ASIC expression is associated with improved survival in glioma patients (Tian et al., 2017). ²Lung: ASICs expressed in human lung cancer cell line A549 determined using RT-PCR, immunofluorescence, and Western blot. Proliferation and migration promoted by overexpression of ASIC1a and inhibited by PcTx1 (Wu et al., 2017). ³Spinal cord: ASICs in human spinal cord, stained with ASIC1 antibody (Arun et al., 2013). ⁴Bone: ASIC expression in human skeleton shown using RT-PCR and antibody staining performed on human chondrocytes (Jahr et al., 2005). ⁵Testis: ASIC3 in human testis based on Northern blot (Ishibashi and Marumo, 1998). ⁶Gut: ASIC2 measured using RT-PCR and immunostaining in human colorectal cancer cells, with ASIC2 promoting cell invasion and proliferation in xenografts (worsened via overexpression and impeded with ASIC2 knockout) (Zhou et al., 2017). ⁷Kidney: ASICs found in human proximal tubular cell line using RT-PCR and Western blotting; apoptosis of cells due to ischemia-reperfusion injury reduced by ASIC1a inhibition using PcTx1 (Song et al., 2019). ASIC1, ASIC2 and ASIC3 protein expression in patients with Henoch-Schönlein purpura nephritis; ASIC blockade with amiloride reduced expression of damage marker proteins (Yuan et al., 2010). ⁸Heart: Transcriptomics revealed presence of ASIC1a in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs); ASIC1a inhibition with Hi1a or PcTx1 improved viability of hiPSC-CMs under conditions of hypoxia and acidosis, whereas viability was further reduced in the presence of the ASIC1a activator MitTx (Redd et al., 2021). ⁹Eye: ASIC1a detected in retinal pigment epithelial cells using RT-PCR and Western blotting; PcTx1 protects cells from oxidative stress (Tan et al., 2013). ASIC3 mRNA detected using RT-PCR on human retina samples (Maubaret et al., 2002). ¹⁰Ear: Presence of ASIC4 shown using RT-PCR and Northern blot (Gründer et al., 2000).

FIGURE 2

Progression of secondary damage after physical damage is inflicted on the spinal cord. Blood flow is restricted as a result of damaged blood vessels, causing tissue acidification and subsequent activation of ASICs.

FIGURE 3

Immune cell lineages in the periphery.

FIGURE 4

Immune cell lineages in the CNS.

FIGURE 5

Function, ASIC profile, and putative role of ASICs in CNS immune cells.