Calcium-activated chloride channel regulator 1 (CLCA1): More than a regulator of chloride transport and mucus production

Cong-Lin Liu,Guo-Ping Shi

doi:10.1016/j.waojou.2019.100077

Cong-Lin Liu, Guo-Ping Shi

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https://doi.org/10.1016/j.waojou.2019.100077

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CLCA1 is a member of the CLCA (calcium-activated chloride channel regulator) family and plays an essential role in goblet cell mucus production from the respiratory tract epithelium. CLCA1 also regulates Ca2+-dependent Cl− transport that involves the channel protein transmembrane protein 16A (TMEM16A) and its accessary molecules. CLCA1 modulates epithelial cell chloride current and participates in the pathogenesis of mucus hypersecretory-associated respiratory and gastrointestinal diseases, including asthma, chronic obstructive pulmonary disease, cystic fibrosis, pneumonia, colon colitis, cystic fibrosis intestinal mucous disease, ulcerative colitis, and gastrointestinal parasitic infection. Most studies have been focused on the expression regulation of CLCA1 in human specimens. Limited studies used the CLCA1-deficient mice and CLCA1 blocking agents and yielded inconsistent conclusions regarding its role in these diseases. CLCA1 not only regulates mucin expression, but also participates in innate immune responses by binding to yet unidentified molecules on inflammatory cells for cytokine and chemokine production. CLCA1 also targets lymphatic endothelial cells and cancer cells by regulating lymphatic cell proliferation and lymphatic sinus growth in the lymphatic organs and controlling cancer cell differentiation, proliferation, and apoptosis, all which depend on the location of the lymphatic vessels, the type of cancers, the presence of Th2 cytokines, and possibly the availability and type of CLCA1-binding proteins. Here we summarize available studies related to these different activities of CLCA1 to assist our understanding of how this secreted modifier of calcium-activated chloride channels (CaCCs) affects mucus production and innate immunity during the pathogenesis of respiratory, gastrointestinal, and malignant diseases.

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Mucin secretion in the Cystic fibrosis (CF) colon depended on the CFTR expression and associated with the production of mCLCA1.81 It was shown that the expression of mCLCA1 was significantly downregulated in small intestines from congenic C57BL/6 CF mice.[82]
In TgrIFABP-mCLCA1 transgenic mice, where mCLCA1 expression was driven by the rat intestinal fatty acid binding protein promoter that is specific to intestinal enterocytes and goblet cells,[83] up-regulation of mCLCA1 resulted in significant improvement of the mucous-based intestinal lesions and disease amelioration.[82]
calcium-activated chloride channel regulator 1 (CLCA1) as a regulator of Ca2þ-activated chloride ion transport on epithelial cells, mucin expression from goblet cells, cytokine and chemokine expression from monocytes and macrophages, tumor cell migration and metastasis, and proliferation of lymphatic endothelial cells (ECs), it has been tested in respiratory diseases, gastrointestinal diseases, cancers, and lymphatic tissue remodeling in humans and experimental models (Table 1)

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In murine experimental acute pneumonia induced by S. aureus infection, the expression of airway mucus component bactericidal/permeability-increasing protein (BPI) fold-containing family A member 1 (Bpifa1), a secretory protein from the respiratory tract that has antimicrobial and anti-biofilm properties to regulate mucociliary clearance,[55] was significantly intensified in Clca1À/À mice compared to that from WT mice at 24 hours post-infection.[56] the role of CLCA1 in respiratory diseases might involve much more complicated downstream pathways, rather than just goblet cell mucus production and epithelial cell chloride ion secretion.

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