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      Calcium-Sensing Receptor of Immune Cells and Diseases

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            Abstract

            Calcium-sensing receptor (CaSR), which was initially found in the parathyroid gland, is ubiquitously expressed and exerts specific functions in multiple cells, including immune cells. CaSR is functionally expressed on neutrophils, monocytes/macrophages, and T lymphocytes, but not B lymphocytes, and regulates cell functions, such as cytokine secretion, chemotaxis, phenotype switching, and ligand delivery. In these immune cells, CaSR is involved in the development of many diseases, such as sepsis, cryopyrin-associated periodic syndromes, rheumatism, myocardial infarction, diabetes, and peripheral artery disease. Since its discovery, it has been controversial whether CaSR is expressed and plays a role in immune cells. This article reviews current knowledge of the role of CaSR in immune cells.

            Main article text

            Introduction

            The extracellular calcium-sensing receptor (CaSR) is an approximately 120–160 kDa G protein–coupled receptor that was initially found in the parathyroid gland and is expressed in many other cell types and organs, such as cardiomyocytes [1], fibroblasts [2], aortic smooth muscle cells [3], and adipocytes [4]. The human CaSR gene (CASR) is located on 3q13.3-21 [5]. As a responder to changes in extracellular Ca2+ concentrations, CaSR plays a primary role in regulating parathyroid hormone secretion and parathyroid hyperplasia. To date, activation of CaSR has been found to be involved in multiple different functions, including secretion [6], proliferation, differentiation, apoptosis, and chemotaxis [7], in various cell types [6, 8]. Even nearly three decades after its initial identification, new functions and mechanisms are still being attributed to CaSR beyond simply a response to physiological Ca2+ concentrations. The expression and function of CaSR on immune cells have recently become a hot topic. However, since its discovery, it has been controversial whether CaSR is expressed and plays a role in immune cells. This article reviews current knowledge of CaSR, CaSR-mediated signaling pathways, the relationship between CaSR and immune cells, and the role of CaSR in disease.

            Structure of CaSR

            CaSR, which was first cloned in 1993, is a member of class C of the G protein–coupled receptors that responds to multiple extracellular cations, such as H+, Na+, Ca2+, and Mg2+ [9]. CaSR is largely expressed and dimerized on the cell membrane, and consists of three protein functional domains. Acting as a ligand-binding domain, the extracellular domain of CaSR binds to numerous physiological ligands, including Ca2+ and other polyvalent species [10]. The seven-transmembrane domain couples CaSR to activating or inhibitory G-proteins, which transduce intracellular signals [11]. CaSR is linked to the cytoskeleton by an intracellular domain, which localizes the receptor to caveolae by binding filamin A [12].

            Gene Encoding CaSR

            The human CaSR gene (CASR) is located on 3q13.3-21 [5]. In contrast, CASR genes in rat, mouse, and bovine species are located on chromosomes 11, 16, and 1, respectively [5, 13]. The human CASR gene contains eight exons, seven of which encode the extracellular domain and untranslated regions, while the seven-transmembrane domain and the carboxy terminus are both encoded by the seventh exon [5, 14]. CaSR contains 1078 amino acids, which are encoded by its fully processed mRNA. The extracellular domain, which is hydrophilic, is composed of 612 amino acids and forms the amino terminus to bind the ligand. The hydrophobic seven-transmembrane domain is composed of approximately 250 amino acids. The exceptionally long intracellular domain of CaSR is composed of 217 amino acids and forms the carboxy terminus [15]. Some human diseases, such as familial hypocalciuric hypercalcemia syndromes [16] and familial hyperparathyroidism [17], have been linked to mutations in CASR.

            CaSR Signaling

            CaSR signaling has been extensively reviewed by Hofer and Brown [18] and Ward [19]. Briefly, many heterotrimeric G proteins, including Gαq/11, Gαi/0, Gα12/13, and Gαs, are involved in the activation of CaSR downstream signaling. When CaSR interacts with Gαq/11, it activates phospholipase C (PLC) and phospholipase D. Inositol trisphosphate (IP3) and diacylglycerol are formed after the activation of PLC. Acting as second messengers, they consequently lead to an increase of intracellular Ca2+ concentrations via the activation of IP3 receptors and subsequent protein kinase C isoforms. Downstream of CaSR, PLC, which is activated by Gαq/11, induces extracellular signal–regulated kinase 1 (ERK1) and ERK2 (also known as p42 and p44 mitogen-activated protein kinase (MAPK), respectively) [20, 21]. CaSR may also stimulate MAPK via β-arrestin proteins but not by a G protein–dependent mechanism [22]. When interacting with Gα12/13, CaSR can modulate cytoskeletal functions and smooth muscle cell contraction by activation of monomeric Rho GTPases [23]. Cellular cyclic AMP, which is activated by adenylate cyclase and acts as a second messenger, is inhibited or activated when CaSR interacts with Gαi/0 or Gαs, respectively. As a G protein that inhibits CaSR, Gαi/0 plays a role in reducing the open probability of Ca2+ channels by inducing the opening of K+ channels [24, 25].

            The expression of CaSR on the cell surface is determined by its signal transduction by an agonist-driven insertional signaling as well. Through this process, it increases the anterograde trafficking of newly synthesized CaSRs to the plasma membrane, and even in response to continual exposure to extracellular Ca2+, agonist-driven insertional signaling can prevent CaSR from undergoing functional desensitization [26, 27] (Figure 1). CaSR-mediated signaling also occurs through the σ subunit of the heterotetrameric AP2 complex; its germ line mutations have been shown to impair intracellular Ca2+ and MAPK signaling responses in CaSR-expressing cells and to cause hypercalcemia [2831]. Through the above-mentioned signaling, CaSR can modulate different physiological functions in calcitropic and noncalcitropic tissues [32]. In calcitropic tissues, CaSR activity and/or signaling can regulate the level of intracellular Ca2+, while in noncalcitropic tissues, downregulation of CaSR activity and signaling is involved in disorders ranging from impaired wound healing to vascular calcification and colorectal carcinoma [3335]; moreover, upregulation of CaSR activity and signaling has been associated with brain injury or asthma [36, 37], and further contributes to disease progression. However, the immune cell–specific CaSR signaling pathway has not been identified, and further studies are needed.

            Figure 1

            Proposed Calcium-Sensing Receptor (CaSR)-Mediated Signal Transduction Pathway.

            Schematic of CaSR, which consists of an extracellular domain (ECD), an intracellular domain (ICD), and a seven-transmembrane domain (7-TMD), at the plasma membrane. CaSR is activated by numerous agonists. When CaSR interacts with Gαq/11, it activates phospholipase C (PLC) and phospholipase D (PLD). Inositol trisphosphate (IP3) and diacylglycerol (DAG) are formed after the activation of PLC. Intracellular Ca2+ concentration increases via the activation of IP3-interacting IP3 receptors (IP3R). Downstream of CaSR, PLC, which is activated by Gαq/11, induces mitogen-activated protein kinase (MAPK) via DAG and subsequently activated protein kinase C (PKC). CaSR may also stimulate MAPK via β-arrestin proteins. When interacting with Gα12/13, CaSR activates Rho GTPase guanine nucleotide exchange factor (Rho GEF) to Ras homolog gene family member A protein (RhoA). Cellular cyclic AMP (cAMP), which is activated by adenylate cyclase (AC), is inhibited or activated when CaSR interacts with Gαi/0 or Gαs, respectively. The expression of CaSR on the cell surface is determined by its signal transduction by an agonist-driven insertional signaling (ADIS). ER, endoplasmic reticulum.

            CaSR of Immune Cells and Diseases

            CaSR of Neutrophils and Diseases

            During different infectious conditions, it is important for the immune system that diverse immune cells are mobilized to the sites of infection to promote immune defense. Neutrophils act as the earliest infiltrating inflammatory cells to defend against infection: the inflammatory signals are sensed, prioritized, and integrated into a migratory response by these cells through phagocytosis and degranulation [38]. The expression and function of CaSR in peripheral blood polymorphonuclear neutrophils (PMNs) had not been described until a study published by Zhai et al. [39] in 2017. They observed, for the first time, that CaSR was expressed in PMNs of rats [39], and not long after, our team detected the expression of CaSR in PMNs of humans [40]. In the study of Zhai et al., the activation of CaSR in PMNs decreased their apoptosis and production of reactive oxygen species and IL-10, and increased the secretion of IL-6 and myeloperoxidase [39]. This revealed that CaSR can delay the apoptosis of PMNs so that they can combat the pathogen for a long time, and CaSR promoted release of proinflammatory cytokines through nuclear factor κB (NF-κB) signaling to amplify the inflammatory response. These findings suggested that CaSR could be used to regulate the immune function of PMNs to reduce inflammatory damage, and CaSR may be a target for the prevention and treatment of inflammatory diseases. However, the role of CaSR in PMNs in specific diseases needs to be further determined in animal studies.

            To date, we have investigated the role of CaSR in neutrophils only in models of myocardial infarction (MI). In humans and rats with MI, we observed the upregulation of CaSR and activation of NLRP3 inflammasome-mediated inflammatory factor IL-1β in PMNs, which was formed by the activation of NLRP3 inflammasome–mediated caspase 1, in PMNs, and this upregulation peaked on day 1 and gradually decreased until day 7. This indicated the neutrophil CaSR was expressed early in both rat and human PMNs and rat myocardium in the MI wound healing. The role of CaSR-activated PMNs in myocardium was investigated by co-culture of PMNs in conditioned medium with cardiomyocytes and cardiac fibroblasts. The results demonstrated that the CaSR-stimulated PMNs aggravated the apoptosis of cardiomyocytes by modulation of the proapoptotic or antiapoptotic proteins, and promoted the differentiation of cardiac fibroblasts into myofibroblasts and the upregulation of collagen secretion [40]. These findings proved that the CaSR-activated PMNs specifically promoted the reparative cardiac remodeling by IL-1β/IL-1 receptor in the first few days of MI, and this may provide a basis for CaSR to be a therapeutic target for cardiac remodeling after MI. However in that study, we did not study the direct effects of PMNs on cardiomyocytes and cardiac fibroblasts. Overall, there is little research on the function of CaSR in PMNs, and its role and mechanism in disease are poorly understood and should be further studied.

            CaSR of Monocytes/Macrophages and Diseases

            After the recruitment of neutrophils, monocytes differentiate into macrophages or dendritic cells and are recruited to sites of inflammation to clear pathogens [41]. The study of CaSR expression in monocytes began in 1997. Because of bone turnover, cells in the bone marrow niche are exposed to substantial changes in extracellular Ca2+ concentration. House et al. [42] performed the first study to determine the expression of CaSR in bone marrow cells. They found that CaSR is expressed in low-density mononuclear bone marrow cells and in several hematopoietic lineage cells. In the following year, Yamaguchi et al. [43] reported that human peripheral blood monocytes express CaSR, which could play a direct role in regulation of extracellular Ca2+ concentration as previously described in the parathyroid gland. The expression of CaSR in monocytes/macrophages has been examined in many monocyte/macrophage cell lines, such as J774 cells [44], RAW 264.7 cells [45], and THP-1 cells [46], which were reported to express functional CaSR and to regulate cytokine secretion through the NF-κB and PLC-IP3 pathways. In response to treatment with phorbol 12-myristate 13-acetate or 1,25-dihydroxyvitamin D3, human promyelocytic leukemia cells (HL-60), which express both CaSR protein and CaSR mRNA, could differentiate into a monocyte/macrophage phenotype in which process the expression of CaSR was increased at the level of translation [47]. These studies suggest that CaSR is expressed on monocytes/macrophages and promotes cytokine secretion. These results provide a theoretical and experimental foundation for the functional study of CaSR on monocytes/macrophages.

            As a pivotal component of innate immunity, macrophages play an important role in homeostasis and disease control. Macrophages are recruited to sites of cell death, which is a key process to induce an immunological response. Extracellular Ca2+ produces a chemoattractant effect through the activation of CaSR via the phosphoinositide 3-kinase (PI3K)-Akt pathway [48]. CaSR increases monocyte chemotaxis in a dose-dependent manner, and monocytes deficient in CaSR lack the normal chemotaxis to a Ca2+ gradient in mice. CaSR-activated monocytes augment the transmigration response to monocyte chemotactic protein 1 (MCP-1), while MCP-1-stimulated monocytes reciprocally increase CaSR expression. The findings suggest CaSR and chemokines interact in a dual-enhancing manner in the recruitment of inflammatory cells [49].

            Macropinocytosis constitutively occurs in macrophages and supports the uptake of antigens for presentation. CaSR senses extracellular Ca2+ and transduces signals to activate macropinocytosis through PI3K and PLC, and CaSR induces constitutive macropinocytosis to promote the sentinel function, which facilitates the efficient delivery of ligands to cytosolic pattern-recognition receptors of macrophages [50]. CaSR participates in the switching of macrophage phenotypes in response to β-tricalcium phosphate extracts (a model biomaterial) and promotes material-stimulated osteogenesis [51]. These results reveal that CaSR is involved in monocyte/macrophage chemotaxis, macropinocytosis, and phenotype switching. CaSR on monocytes/macrophages is associated with many diseases, such as peripheral artery disease, rheumatoid arthritis, cryopyrin-associated periodic syndromes, MI, obesity-related metabolic disorders, and osteoarthritis. A nearly 1.5-fold increased expression of CaSR in the monocytes of patients with peripheral artery disease and diabetes was observed during the posttranscription and was related to the concentrations of glucose and proinflammatory cytokines and the severity of peripheral artery disease [52]. Similarly to the role of CaSR on monocytes in peripheral artery disease patients, the expression of CaSR in monocytes is upregulated in rheumatoid arthritis patients with severe coronary artery calcification [53]. Both studies show that CaSR expression on monocytes is associated with disease severity, so the detection of CaSR expression on human peripheral blood monocytes could be used as an effective method to monitor many diseases. However, whether there is temporal relationship between CaSR expression and atherosclerosis remains to be clarified.

            In cryopyrin-associated periodic syndromes, which are induced by mutations of the NLRP3 gene that lead to a series of autoinflammatory diseases, CaSR activates the NLRP3 inflammasome by increased intracellular Ca2+ concentration and decreased cyclic AMP concentration, and this process promotes the secretion of proinflammatory cytokines in bone marrow–derived macrophages and peripheral monocytes [54]. In our own work, CaSR was found to be expressed on both M1 macrophages, and M2 macrophages, but only CaSR expressed on M1 macrophages induces IL-1β secretion by NLRP3 inflammasome activation via the PLC-IP3 pathway, and this process promotes cardiac remodeling by promoting the phenotypic transformation of cardiac fibroblasts and modulation of collagen, matrix metalloproteinase 2 (MMP2), MMP9, and tissue inhibitor of metalloproteinases 2 (TIMP-2), which was identified by co-culture of cardiac fibroblasts with CaSR-activated or inhibited M1 macrophage supernatants [55]. These findings indicate that CaSR-mediated macrophage-specific promotion of reparative cardiac remodeling lasts as long as 14 days after MI. Therefore, it can be seen that macrophages are the dominant cells in the process of cardiac repair after MI, and CaSR intervention on macrophages may be one of the methods to regulate adverse ventricular remodeling after MI.

            Obesity is a worldwide health problem, because it leads to obesity-related metabolic disorders, such as cardiovascular disease, type 2 diabetes, and cancer. So, it is very urgent to explore the pathogenesis of obesity-related metabolic disorders. D‘Espessailles et al. [56] investigated the inflammatory mechanism of these disorders. In that study, human LS14 preadipocytes were exposed to conditioned medium consisting of CaSR-activated or inhibited macrophages that were differentiated from THP-1 monocytes. It was found that LS14 preadipocytes could secrete proinflammatory cytokines under the action of CaSR-stimulated macrophages, which resulted in increased secretion of inflammatory markers and activation of the NLRP3 inflammasome by CaSR activation on these macrophages themselves [56]. These findings suggest that upregulation of CaSR on macrophages not only promotes the proinflammatory features by positive feedback but also provokes the inflammatory activity of adipocytes by paracrine signaling. Although these results need to be confirmed in animal models, they suggest it may be possible to prevent obesity-related metabolic disorders by regulating CaSR function on macrophages in adipose tissue.

            Compared with the other rheumatisms, CaSR expression in osteoarthritis patients was upregulated in monocytes extracted from peripheral blood and synovial fluids, with higher expression in synovial fluids that was associated with the inflammatory nature of the synovial fluid [57]. These findings demonstrate that in patients with rheumatism with synovial fluid, extraction of monocytes from the synovial fluid and detection of CaSR expression can not only provide important help for the diagnosis of osteoarthritis but can also reflect the inflammatory characteristics of the synovial fluid; moreover, monocytes may be a potential therapeutic target by the use of CaSR allosterizers.

            CaSR of Lymphocytes and Diseases

            In an inflammatory microenvironment, homologous antigens carried by antigen-presenting cells (APCs) are followed or found by T lymphocytes by modifying their migration [58]. Once the T lymphocytes recognize the antigens on the APC, the resulting binding synergistically activates the T lymphocytes [59]. The experiments performed to determine CaSR expression in bone marrow cells by House et al. in the 1990s indicated that CaSR is expressed in low-density mononuclear bone marrow cells and in several hematopoietic lineage cells, while it was ambiguous whether CaSR is expressed in peripheral blood polymorphonuclear leukocytes [42]. Fifteen years later, Li et al. [60] confirmed the protein and mRNA expression of CaSR in human peripheral blood T lymphocytes and reported that activator of CaSR (Gd3+ and Ca2+) promoted the secretion of proinflammatory cytokines (IL-6 and lymphotoxin) in a concentration-dependent manner through the partial MAPK and NF-κB pathways [60]. These findings revealed that the immune regulation effect of CaSR on T cells may be realized by regulating intracellular signal and cytokine products, and further research is needed to determine whether regulation of CaSR function on T cells can be a method to treat the disease.

            As inflammatory cells, the role of T lymphocytes in some inflammatory and sterile diseases, such as sepsis and MI, has been studied. In sepsis, upregulation of CaSR was observed in T lymphocytes of rats with sepsis. T lymphocytes obtained from rats with sepsis were exposed to activator and inhibitor of CaSR to study the function of CaSR in sepsis. It was found that increased CaSR expression could promote the secretion of proinflammatory (TNF) and anti-inflammatory (IL-4) factors and apoptosis of T lymphocytes through the partial MAPK and NF-κB pathways [61]. Although elevated CaSR expression promoted the expression of both proinflammatory and anti-inflammatory cytokines in sepsis, the analysis of the ratio of the two types suggests that proinflammatory cytokines are predominant in CaSR-induced secretion of inflammatory cytokines. In the same year, the same research team also found that activated CaSR on T lymphocytes could increase the expression of transient receptor potential channel 3 (TRPC3) 3 and TRPC6 through the PLC-IP3 pathway, thereby synergistically increasing the intracellular Ca2+ concentration and promoting the apoptosis of T lymphocytes in sepsis [62]. Therefore, inhibiting CaSR to reduce the apoptosis of T lymphocytes and the predominant secretion of proinflammatory cytokines in sepsis may be an effective method to increase the survival rate of patients with sepsis.

            MI is a sterile response in which lymphocytes play an important role [63]. Zeng et al. [64] conducted the first study on the role of CaSR in MI. In acute MI and percutaneous coronary intervention (PCI) patients, increased CaSR expression, cytokine secretion, and apoptosis were observed in the T lymphocytes, and these results were probably associated with the NF-κB pathway. In these patients, CaSR promotes both proinflammatory and anti-inflammatory cytokines in T lymphocytes, which is similar to the case in sepsis, and the levels of proinflammatory cytokines decline more quickly than those of anti-inflammatory cytokines. This means that CaSR on T lymphocytes plays a role in both the early injury stage and the late repair stage in MI. Moreover, the apoptosis ratio of T lymphocytes increased obviously at the onset of acute MI and on the first day of PCI, and it then returned to the baseline gradually on the third day of PCI. The expression of CaSR on T lymphocytes after MI is related to the stage of the disease and the state of the inflammatory response; therefore, specific regulation of CaSR can avoid unnecessary damage after MI. It was reported that expression of CaSR in cardiomyocytes was positively correlated with the sensitivity to MI in atherosclerotic rats [65]. Zeng et al. [66] clarified the causal relationship between CaSR in T lymphocytes and MI. When hypoxic/reoxygenated mouse cardiomyocytes were co-cultured with human peripheral blood T lymphocytes or CaSR-silenced T lymphocytes, necrosis and apoptosis of cardiomyocytes, cytokine secretion, and the levels of MAPK pathway–related proteins of T lymphocytes were significantly increased or reversed. These findings demonstrate that CaSR on T lymphocytes promotes cardiomyocyte injury and damaged cardiomyocytes promote the activation of CaSR on the T lymphocytes and the secretion of cytokines to amplify the inflammatory reaction. This reciprocal process is vital to MI development.

            Ca2+ in the environment plays an important role in the immune response of B lymphocytes. However, B lymphocytes can neither express CaSR nor be inhibited by CaSR-specific inhibitors, so it is believed that the calcium receptor of B lymphocytes is not conventional CaSR [67].

            These studies suggest that CaSR on T lymphocytes contributes to cytokine secretion and apoptosis, which play important roles in sepsis and MI. Although current studies have shown that CaSR on T lymphocytes regulates cytokine release and apoptosis of T cell subsets, whether it affects the phenotypic differentiation and changes in the proportions of T cell subsets and whether it plays a role in other diseases still require further study.

            CaSR and Immune Cell Migration

            Immune cell migration is essential in the immune response and inflammation (see Table 1). In addition to the functions of CaSR described above, CaSR is required for mineral trioxide aggregate (MTA)-induced cell migration in human acute T-cell leukemia cell Jurkat cells, THP-1 cells, human neutrophil-like HL-60 cells, human U937 monocytes, and mouse CD4+ T cells. The CaSR-PI3K-CDC42 cascade and the CaSR–PLCγ–myosin light chain kinase cascade regulate MTA-induced cell chemotaxis and chemokinesis, respectively [68]. Therefore, when tissue damage occurs, MTA can promote the recruitment of immune cells to the damaged site through CaSR on immune cells so as to promote the immune response and injury healing, and CaSR may become an important target for regulating the migration of immune cells in different diseases.

            Table 1

            Expression of, Functions of, and Diseases Related to Calcium-Sensing Receptor in Immune Cells.

            Immune cellsDiscovery yearFunctionsDiseases
            Neutrophils2017 [39]Cytokine secretion [39]MI [40]
            Cell migration [68]
            Monocytes/macrophages1997 [42]Cytokine secretion [44]Peripheral artery disease [52]
            Chemotaxis [48]Rheumatoid arthritis [53]
            Macropinocytosis [50]CAPS [54]
            Phenotype switch [51]MI [55]
            Cell migration [68]Obesity-related metabolic disorder [56]
            Osteoarthritis [57]
            T lymphocytes2013 [60]Cytokine secretion [60]Sepsis [61, 62]
            Cell migration [68]MI [64, 66]

            CAPS, cryopyrin-associated periodic syndromes; MI, myocardial infarction.

            Conclusions and Future Perspectives

            CaSR, which was initially identified in the parathyroid gland, is ubiquitously expressed and exerts specific functions in multiple cells. The main role of CaSR is to regulate calcium homeostasis, but an increasing number of studies have also investigated its role in non-calcium-regulating cells. We have reviewed the expression and role of CaSR in some immune cells (Table 1); however, the expression and role of CaSR have not been studied in natural killer cells, dendritic cells, eosinophils, basophils, and mast cells of the immune system. Current studies have shown that CaSR on immune cells is involved in a variety of disease processes. However, the roles and mechanisms of CaSR in other diseases need to be studied further to provide a basis for its use as an effective target for the treatment of these diseases.

            Acknowledgments

            This study was supported by the National Natural Science Foundation of China for Xinhua Yin and Wenxiu Liu (81370319 and 81700318), the China Postdoctoral Science Foundation for Wenxiu Liu (2018M631957), the Hei Long Jiang Postdoctoral Fund for Wenxiu Liu (LBH-Z17145), Doctor Funds of the First Affiliated Hospital of Harbin Medical University for Wenxiu Liu (201613007), and the Innovation and Entrepreneurship Training Program for College Students of Harbin Medical University for Wenxiu Liu (201910226157).

            Conflicts of Interest

            The authors declare that they have no conflicts of interest.

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            Author and article information

            Journal
            CVIA
            Cardiovascular Innovations and Applications
            CVIA
            Compuscript (Ireland )
            2009-8782
            2009-8618
            May 2021
            May 2021
            : 5
            : 4
            : 257-266
            Affiliations
            [1] 1Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001 Heilongjiang, China
            Author notes
            Correspondence: Wenxiu Liu and Xinhua Yin, Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, No. 23, YouZheng Street, NanGang District, Harbin, 150001, China, E-mail: hitlqn@ 123456126.com ; yinxinhua5063@ 123456163.com
            Author information
            https://orcid.org/0000-0002-8835-5556
            https://orcid.org/0000-0003-2208-8341
            Article
            cvia.2021.0009
            10.15212/CVIA.2021.0009
            4289998a-3d8d-43af-aafa-bc4d6e8746ce
            Copyright © 2021 Cardiovascular Innovations and Applications

            This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 Unported License (CC BY-NC 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See https://creativecommons.org/licenses/by-nc/4.0/.

            History
            : 20 November 2020
            : 27 January 2021
            : 3 February 2021
            Categories
            Research Papers

            General medicine,Medicine,Geriatric medicine,Transplantation,Cardiovascular Medicine,Anesthesiology & Pain management
            T lymphocyte,monocyte/macrophage,Calcium-sensing receptor,B lymphocyte,neutrophil

            Comments

            wrote:

            钙敏感受体(Calcium sensing receptor,CaSR)最初在甲状旁腺被发现,之后证实其在组织和细胞中广泛表达并发挥生物学效应。近年来,CaSR被发现在中性粒细胞、单核/巨噬细胞和T淋巴细胞上功能性表达,但在B淋巴细胞上不表达,参与免疫细胞的功能调节,例如:细胞因子分泌、趋化、表型转换和抗原呈递。免疫细胞CaSR的活化参与了许多疾病的发生发展,如脓毒症、cryopyrin相关周期性综合征、风湿病、心肌梗死(Myocardial infarction,MI)、糖尿病和外周动脉疾病等。为此,我们对对免疫细胞CaSR的表达及功能进行了梳理,并对其在相关疾病中的研究进展做一综述发表在《Cardiovascular Innovations and Applications》。

            我们首先阐述了CaSR的编码基因、结构和功能以及其可能的信号传导通路。CaSR基因定位于3q13.3-21(人类),由细胞外结构域、七次跨膜结构域和胞内结构域构成,属于G蛋白偶联受体超家族,被证实在多个系统的细胞(包括免疫细胞)广泛表达发挥多种生物学效应。CaSR的信号传导通络与Gαq/11、Gαi/0、Gα12/13和Gαs等G蛋白功能调节有关:CaSR与Gαq/11结合时可激活PLC-IP3信号通路从而增加胞内钙浓度;与Gα12/13激活则激活单体Rho GTP酶调节细胞骨架功能和平滑肌细胞收缩,而与Gαi/0和Gαs相互作用时则可降低钙通道开放概率。

             

            我们还阐述免疫细胞的CaSR表达和功能:中性粒细胞上CaSR的激活降低其凋亡、ROS和IL-10的产生,增加IL-6和髓过氧化物酶的分泌,进一步研究发现此过程是NF-κB信号通路介导的。2020年,我们的团队首先报道了中性粒细胞上CaSR参与MI的发病过程。与中性粒细胞相比较,CaSR在单核/巨噬细胞中的研究较早,研究发现它既促进细胞因子分泌外,又增加单核/巨噬细胞趋化、巨胞饮和表型转化。单核/巨噬细胞上的CaSR与许多疾病有关,如外周动脉疾病、类风湿性关节炎、cryopyrin相关周期性综合征、MI、肥胖相关代谢紊乱和骨关节炎等。而T淋巴细胞的CaSR活化则能通过部分MAPK和NF-κB途径促进促炎细胞因子(IL-6和TNF-β)的分泌,在一些炎性和无菌性疾病中发挥作用,如脓毒症和MI。

             

            文中提及CaSR在以上三种免疫细胞中功能性表达,并均在MI中发挥重要作用。在MI患者和大鼠中,外周血中性粒细胞(Peripheral blood polymorphonuclear neutrophils,PMN)上检测到CaSR表达上调,同时由其介导的NLRP3炎性体活化形成的IL-1β分泌增加。

             

            然而,中性粒细胞究竟对心肌细胞和成纤维细胞发挥什么样的作用呢?通过PMN条件培养基与心肌细胞和心肌成纤维细胞共培养发现,CaSR刺激PMN通过调节促凋亡或抗凋亡蛋白加重心肌细胞的凋亡,并促进心脏成纤维细胞向肌成纤维细胞的分化和胶原分泌,提示特异性地抑制中性粒细胞CaSR可能成为防治MI后心脏重塑的新策略。

             

            总体而言,CaSR在PMN中的功能研究甚少,其在疾病中的作用和机制知之甚少,应进一步研究。巨噬细胞是MI后免疫反应的主导细胞。我们的团队对CaSR在MI中的作用进行了研究,结果表明MI后心肌组织浸润的巨噬细胞和腹腔巨噬细胞CaSR表达上调,并可通过PLC-IP3途径和自噬途径促进巨噬细胞NLRP3炎性体活化,从而促进炎性细胞因子IL-1β分泌。进一步的研究发现,CaSR活化的M1型巨噬细胞可促进心脏成纤维细胞的表型转化、基质蛋白酶和胶原分泌,从而促进心室重塑。因此,巨噬细胞是MI后心脏修复过程中的优势细胞,CaSR干预巨噬细胞可能是调节MI后不良心室重构的方法之一。

            在急性MI和经皮冠状动脉介入(Percutaneous coronary intervention,PCI))治疗患者中,T淋巴细胞CaSR表达、细胞因子分泌和细胞凋亡增加,均与NF-κB通路有关。在这些患者中,CaSR促进T淋巴细胞中的促炎和抗炎细胞因子,促炎细胞因子比抗炎细胞因子下降迅速,提示T淋巴细胞上的CaSR在MI的损伤早期和修复晚期均起作用。此外,T淋巴细胞的凋亡率在急性MI发作时和PCI第1天明显增加,然后在PCI第3天逐渐恢复到基线,表明MI后T淋巴细胞上CaSR的表达与疾病的分期和炎症反应的状态有关,因此,特异性调节CaSR可以避免MI后不必要的损伤。缺氧/复氧小鼠心肌细胞与人外周血T淋巴细胞或CaSR沉默的T淋巴细胞共培养时,心肌细胞的坏死和凋亡、细胞因子分泌和T淋巴细胞的MAPK通路相关蛋白显著增加或逆转,表明T淋巴细胞上的CaSR促进心肌细胞损伤,受损的心肌细胞促进T淋巴细胞上CaSR的活化和细胞因子的分泌以放大炎症反应,这一相互过程对MI的发生至关重要。

             

            至今,CaSR发现已近30年,CaSR在多种细胞和疾病中发挥重要作用。我们对免疫细胞CaSR的表达与功能以及其在相关疾病中的研究进展进行综述,为CaSR在细胞和疾病中的新作用研究提供重要线索。而且,该文还指出目前仍有大量其他免疫细胞CaSR的表达及功能尚待研究,同时免疫细胞CaSR在很多疾病中的作用和机制仍不清楚,需要进一步研究去探索。

             

            2021-07-01 02:30 UTC
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