Increased intracellular Cl− concentration promotes ongoing inflammation in airway epithelium

Zhang, Yilin; Chen, Peng-Xiao; Guan, Weijun; Guo, Hongmei; Qiu, Zhen; Xu, Jiawen; Luo, Yu-Li; Lan, Chong-Feng; Xu, Jian-Bang; Hao, Yuan; Tan, Ya-xia; Ke-nan, YE; Lun, Zhao‐Rong; Zhao, Lei; Zhu, Yun-Xin; Huang, Jiehong; Ko, Wing‐Hung; Zhong, Weijie; Zhou, Wen‐Liang; Zhong, Nanshan

doi:10.1038/s41385-018-0013-8

Cited by 52 publications

(71 citation statements)

References 64 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Something similar occurs with WNK Cl − sensors, which are negatively modulated by increased [Cl − ] (Sun et al ., ). However, SGK1 showed a response to Cl − similar to that seen for IL‐1β, in which the activity increased with [Cl − ]; in both cases in the presence of nigericin and tributyltin (Clauzure et al ., ; Zhang et al ., ). We cannot explain these apparent discrepancies, but perhaps the membrane potential changes when the [Cl − ] e is modified, displacing the biphasic Cl − curve towards lower [Cl − ] such that a reduction in the [Cl − ] i increases the expression of JNK and IL‐1β‐associated responses.…”

Section: Cl− As a Signalling Effector For Cftrmentioning

confidence: 97%

“…Intriguingly, increasing Cl − concentration has opposing effects on WNK1 and SGK1 activities, decreasing the activity of WNK1 and increasing that of SGK1. Direct effects of Cl − on SGK1 structure have not yet been reported, although in vitro incubation with different Cl − concentrations supports a direct dependency with Cl − (Zhang et al, 2018). However, until the effects of Cl − on the 3D structure of SGK1 are demonstrated, an indirect effect of [Cl − ] i changes affecting SGK1 activity or expression cannot be ruled out.…”

Section: (1) Effects Of CL − On Enzymesmentioning

confidence: 99%

“…Zhang et al . () recently showed that serum glucocorticoid regulated kinase 1 (SGK1) activity is under Cl − modulation and that this kinase might be involved in the mechanism by which Cl − acts as a proinflammatory signal (Clauzure et al ., ; Zhang et al ., ). Intriguingly, increasing Cl − concentration has opposing effects on WNK1 and SGK1 activities, decreasing the activity of WNK1 and increasing that of SGK1.…”

Section: Cl− Effects In Eukaryotic Cellsmentioning

confidence: 99%

“…The discovery that WNK kinases act as intracellular Cl − sensors opens a new avenue in the study of the role of Cl − as a second messenger and reveals another pathway of Cl − signalling through the activation of these kinases. Zhang et al (2018) recently showed that serum glucocorticoid regulated kinase 1 (SGK1) activity is under Cl − modulation and that this kinase might be involved in the mechanism by which Cl − acts as a proinflammatory signal Zhang et al, 2018). Intriguingly, increasing Cl − concentration has opposing effects on WNK1 and SGK1 activities, decreasing the activity of WNK1 and increasing that of SGK1.…”

Section: (1) Effects Of CL − On Enzymesmentioning

confidence: 99%

“…The mechanism by which [Cl − ] i modulates IL-1β secretion is unknown. However, a recent study reports a possible central role of SGK1 as a Cl − -dependent kinase, which might be involved in nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation through NF-κB (Zhang et al, 2018).…”

Section: − As a Signalling Effector For Cftrmentioning

confidence: 99%

See 4 more Smart Citations

The chloride anion as a signalling effector

Valdivieso

Santa‐Coloma

2019

Biological Reviews

View full text Add to dashboard Cite

The specific role of the chloride anion (Cl−) as a signalling effector or second messenger has been increasingly recognized in recent years. It could represent a key factor in the regulation of cellular homeostasis. Changes in intracellular Cl− concentration affect diverse cellular functions such as gene and protein expression and activities, post‐translational modifications of proteins, cellular volume, cell cycle, cell proliferation and differentiation, membrane potential, reactive oxygen species levels, and intracellular/extracellular pH. Cl− also modulates functions in different organelles, including endosomes, phagosomes, lysosomes, endoplasmic reticulum, and mitochondria. A better knowledge of Cl− signalling could help in understanding the molecular and metabolic changes seen in pathologies with altered Cl− transport or under physiological conditions. Here we review relevant evidence supporting the role of Cl− as a signalling effector.

show abstract

Section: Cl− As a Signalling Effector For Cftrmentioning

confidence: 97%

Section: (1) Effects Of CL − On Enzymesmentioning

confidence: 99%

Section: Cl− Effects In Eukaryotic Cellsmentioning

confidence: 99%

Section: (1) Effects Of CL − On Enzymesmentioning

confidence: 99%

Section: − As a Signalling Effector For Cftrmentioning

confidence: 99%

See 3 more Smart Citations

The chloride anion as a signalling effector

Valdivieso

Santa‐Coloma

2019

Biological Reviews

View full text Add to dashboard Cite

show abstract

Macrophage dysfunction in cystic fibrosis: Nature or nurture?

Turton

Ingram

Valvano

2020

Journal of Leukocyte Biology

View full text Add to dashboard Cite

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the homeostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respiratory epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTR is, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitive to conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophages by affecting the lung milieu, but the mutations also appear to be directly consequential for intrinsic macrophage functions. Particular mutations can alter CFTR's folding, traffic of the protein to the membrane and function. As such, understanding the intrinsic effects of CFTR mutation requires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from the primary defect of CFTR dysfunction/absence. Investigations into CFTR's role in macrophages have exploited various models, each with their own advantages and limitations. This review summarizes these methodologic approaches, discussing their physiological correspondence and highlighting key findings. The controversy surrounding CFTR-dependent acidification is used as a case study to highlight difficulties in commensurability across model systems. Recent work in macrophage biology, including polarization and host-pathogen interaction studies, brought into the context of CFTR research, offers potential explanations for observed discrepancies between studies. Moreover, the rapid advancement of novel gene editing technologies and new macrophage model systems makes this assessment of the field's models and methodologies timely.

show abstract

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Lara-Reyna

Holbrook

Jarosz-Griffiths

et al. 2020

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Cystic fibrosis (CF) is one of the most common life-limiting recessive genetic disorders in Caucasians, caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF is a multi-organ disease that involves the lungs, pancreas, sweat glands, digestive and reproductive systems and several other tissues. This debilitating condition is associated with recurrent lower respiratory tract bacterial and viral infections, as well as inflammatory complications that may eventually lead to pulmonary failure. Immune cells play a crucial role in protecting the organs against opportunistic infections and also in the regulation of tissue homeostasis. Innate immune cells are generally affected by CFTR mutations in patients with CF, leading to dysregulation of several cellular signalling pathways that are in continuous use by these cells to elicit a proper immune response. There is substantial evidence to show that airway epithelial cells, neutrophils, monocytes and macrophages all contribute to the pathogenesis of CF, underlying the importance of the CFTR in innate immune responses. The goal of this review is to put into context the important role of the CFTR in different innate immune cells and how CFTR dysfunction contributes to the pathogenesis of CF, highlighting several signalling pathways that may be dysregulated in cells with CFTR mutations.

show abstract

Increased intracellular Cl− concentration promotes ongoing inflammation in airway epithelium

Cited by 52 publications

References 64 publications

The chloride anion as a signalling effector

The chloride anion as a signalling effector

Macrophage dysfunction in cystic fibrosis: Nature or nurture?

Dysregulated signalling pathways in innate immune cells with cystic fibrosis mutations

Contact Info

Product

Resources

About