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Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
Amid the several cellular processes that they regulate, CLIC channel activity is also considered to be important for immune cell activation. Bone marrow-derived dendritic cells (BMDCs) isolated from clic1−/− mice showed diminished antigen presentation due to impaired phagosomal acidification148. In DCs, phagocytosis triggered the translocation of cytoplasmic CLIC1 to a phagosomal membrane, where it was shown to regulate phagosomal pH and proteolysis of the antigen148. Pharmacological blockage of the DCs isolated from wild-type mice with CLIC inhibitor indanyloxyacetic acid (IAA-94) also showed a similar defect in their antigen presentation ability, indicating that the channel activity of CLICs contributes to this function148. CLIC1, CLIC4, and CLIC5, as shown in Figure 10.1, are present in the circulating monocytes of mice as well. It was observed that CLIC1 expression increased in PBMCs in chronic inflammatory conditions of the central nervous system, such as Alzheimer’s disease, and can be considered as a potential biomarker for neurodegenerative disease conditions149. The absence of CLIC1 impaired phagosomal acidification and reduced ROS generation in macrophages150,151. CLICs also play a role in NLRP3 inflammasome complex formation by macrophages118,119. NLRP3 is a multiprotein inflammasome complex formed by the innate immune sensor protein NLRP3, adapter protein ASC, and proteolysis enzyme caspase 1152,153. NLRP3 complex formation is required for the secretion of pro-inflammatory cytokines such as IL-1β and IL-18 against stress conditions or upon infection. K+ efflux is known to cause mitochondrial damage, increasing the ROS production by the mitochondria and leading to activation of NLRP3 inflammasome complex154. The mitochondrial ROS generated in this process was shown to induce translocation of CLICs (CLIC1, CLIC4, and CLIC5) to the plasma membrane, leading to chloride efflux and thus contributing to inflammasome assembly and IL-1β secretion118,154. These studies provide substantial evidence that the CLIC-mediated upstream event is a prerequisite for the regulation of NLRP3 activation, and Cl− flux changes facilitated by them play a key role in activating the innate immune system. Because CLICs are mitochondrial ion channel proteins that affect mitochondrial physiology117, their specific role in both innate and adaptive immune cell activation via modulating mitochondrial function needs to be addressed. In addition, the increasing evidence implicating the role of chloride flux changes in immune cell activation, development, and function cannot be ignored, and more attention should be given to the molecular identification of other uncharacterized chloride channels in immune cells.
Effects of CLIC4 on Fucoxanthinol-Induced Apoptosis in Human Colorectal Cancer Cells
Published in Nutrition and Cancer, 2021
Reo Yokoyama, Hiroyuki Kojima, Rie Takai, Tohru Ohta, Hayato Maeda, Kazuo Miyashita, Michihiro Mutoh, Masaru Terasaki
Chloride intracellular channel 4 (CLIC4) is a member of the CLIC family and is ubiquitously expressed in various tissues. CLIC4 is localized particularly in subcellular mitochondria, cytoplasm, and endoplasmic reticulum, and plays essential roles in cellular homeostasis. CLIC4 regulation has been reported in connection with a pivotal tumor suppressor, p53 (1). CLIC4 interacts with Rab35-positive endosome involved in integrin β1 trafficking and with Na+/H+ exchanger regulatory factor 2 (NHERF2), a key molecule for cytoskeleton modulator, and enhances transforming growth factor (TGF)-β signaling, including Smad (2–4). Accordingly, CLIC4 plays an important role in apoptosis, angiogenesis, cell adhesion, and wound healing (2, 5–7). To date, no genetic alterations have been observed in CLICs in any types of cancer patients, except for CLIC1 (8).
Utilizing proteomics to understand and define hypertension: where are we and where do we go?
Published in Expert Review of Proteomics, 2018
Christian Delles, Emma Carrick, Delyth Graham, Stuart A. Nicklin
SHR have been extensively characterized at both the genomic and phenotypic level [55–57], and the model has been used to examine the proteome in a range of cardiovascular tissues. Examples include a study by Jin et al. [58] that examined protein expression changes occurring during development of left ventricular hypertrophy, using 2D gel electrophoresis in combination with matrix assisted laser desorption/ionization – time of flight tandem mass spectrometry (MALDI-TOF/TOF MS/MS) in left ventricular myocardium from SHR and normotensive Wistar Kyoto (WKY) rats. They reported 13 proteins that were differentially expressed in the SHR before the onset of hypertension. These proteins included □-enolase and lactate dehydrogenase B, which are two important enzymes for glycolysis, as well as proteins associated with mitochondrial oxidative phosphorylation, oxidative stress and cellular energy metabolism [8]. In addition, a study by Lee et al. [59] also reported the use of 2D gel electrophoresis and MALDI-TOF/TOF MS/MS to study protein expression profiles in aortic smooth muscle of SHR and WKY rats. They identified seven proteins that were differentially expressed between the strains, including reduced expression of dihydropteridine reductase (DHPR), which is associated with the regeneration of tetra-hydrobiopterin (BH4) and is involved in the development of vascular oxidative stress [60]. A recent study by Hatziioanou et al. [61] that used 2D gel electrophoresis of renal parenchyma from SHR and WKY rats identified overexpression of chloride intracellular channel 4 (CLIC4) protein in the proximal tubule during early stages of hypertension development. This finding suggests that CLIC4 may be a useful early marker to detect renal tubular alterations in the development of hypertensive nephrosclerosis.