微环境酸化通过ASICs调控DC功能
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摘要
酸碱平衡是维持机体内环境稳态的重要环节,正常情况下,外周血和各器官组织的pH约为7.2-7.4。某些病理状态(如炎症、肿瘤和自身免疫病)下,病灶部位酸化(pH下降)是参与相关疾病发生、发展的重要因素。因此,探讨酸化对机体免疫系统(主要是各类免疫细胞)功能的影响,具有重要意义。
抗原提呈细胞(APC)重要的免疫系统组分,在固有免疫和适应性免疫应答中发挥重要作用。树突状细胞(DC)是体内最重要的的专职APC,负责摄取、加工和处理抗原,并将抗原信息提呈给初始T细胞,启动抗原特异性T细胞应答。已证明,DC表面多种膜分子参与抗原提呈过程：DC表面MHC分子与抗原肽结合为复合物(pMHC),将抗原肽提呈给T细胞(产生第一信号)；DC表面CD80或CD86与T细胞表面CD28结合,可提供T细胞激活的第二信号(共刺激信号)。此外,DC也参与多种免疫病理过程(如炎症、肿瘤和自身免疫病等)发生、发展。文献已报道,细胞微环境酸化可促进DC吞噬功能和抗原提呈(MHCⅠ类分子途径),但其确切机制尚不清楚。
酸敏感离子通道(ASICs, acid-sensing ion channels)是一类H+门控的阳离子通道,属上皮钠通道／退化蛋白[ENaC (epithelial sodium channel)/DEG (degenerin)]家族。ASICs主要表达于中枢和外周神经元,与触觉、学习记忆、痛觉和酸味觉形成有关。近年报道,非神经细胞(平滑肌细胞和骨细胞)和淋巴细胞(T细胞)也可表达ASICs,后者参与相关细胞的功能调控。
本研究以小鼠骨髓来源的DC为研究对象,拟探讨重要的专职APC-DC是否表达ASICs,在此基础上,观察微环境酸化对DC的功能调控作用及其与ASICs的关系。
一、DC表达功能性ASICs
1.DC表达ASICs
体外诱导BMDC分化,提取其总RNA和全蛋白,借助RT-PCR和Western blot证明：DC可表达ASIC1、ASIC2和ASIC3的mRNA和蛋白质。借助免疫荧光双标法和免疫电镜胶体金法检测ASIC在DC内的定位,结果显示：ASIC1和ASIC3分别表达于DC内质网和线粒体,细胞膜未见表达；而ASIC2主要表达于胞膜。
2.DC表面ASICs的电生理功能
借助全细胞膜片钳检测DC所表达ASICs的电生理功能,结果显示：细胞外pH6.0可激活DC胞膜表面ASICs样内向电流,该电流包含早期快速激活和晚期慢速失活两个时相,且能被ASICs阻断剂阿米洛利可逆性阻断(n=6,p<0.05)。pH6.0激活的ASICs样电流具有如下特点：平均幅度为329.63±52.36 pA；该内向电流具有pH依赖性：激活电流的最大pH值在7.0左右,产生最大电流的pH值为5.0；pH50为6.08±0.05,Hill系数为1.03±0.07(n=6)。
二、细胞外酸化诱发的DC内向电流依赖于ASICs
1.细胞外酸化诱发的DC内向电流不依赖于TRPV1
瞬时受体电位香草酸亚型1(TRPV1, transient receptor potential vanilloid-1)亦称VR1,属非选择性阳离子通道。细胞外pH值低于6.0,可在细胞膜产生内向电流。以皮层神经元为阳性对照,TRPV1激动剂辣椒素不能诱发DC产生TRPV1电流,提示DC不表达功能性TRPV1。另外,借助RT-PCR也未能在DC检出TRPV1 mRNA表达。上述实验结果提示：细胞外pH值降低诱发DC所产生的电流并非TRPV1介导,其为ASICs依赖性(见前述)。
2.非甾体抗炎药抑制DC表面ASICs的电生理功能
文献报道,非甾体抗炎药可抑制海马和感觉神经元ASICs的功能。本研究借助全细胞膜片钳技术,观察非甾体抗炎药(布洛芬和双氯芬酸)对DC表面ASICs电生理功能的影响。结果显示：布洛芬(200μM)和双氯芬酸(200μM)均可明显降低DC的ASICs电流(前者从364.17±57.15 pA降低为176.07±28.77 pA,抑制率51.49±3.75%；后者从353.97±51.58 pA降低为166.7±18.57 pA,抑制率51.67±8.3%),该抑制效应为可逆性。上述结果提示,非甾体抗炎药可抑制DC表面ASICs的电生理功能。
三、细胞外酸化通过ASICs调控DC功能
1.细胞外酸化通过ASICs上调DC表面抗原提呈相关分子表达
用ASICs阻断剂阿米洛利(100μM)预处理培养7天的DC(30 min,37℃,5%CO2),然后在pH6.5的培养基中培养4 h(37℃,7%CO2),流式细胞术检测DC表面CD11c、MHCIⅡ、CD80和CD86表达。结果显示：与对照组(pH6.5单独刺激4 h)相比,阿米洛利可明显抑制DC表面相关分子表达(n=6,p<0.05),提示微环境酸化可通过ASICs而调控DC表面抗原提呈相关分子表达。
2.非甾体抗炎药通过抑制ASICs功能而影响细胞外酸化对DC表面抗原提呈相关分子表达的调控作用
前面实验结果已证实,非甾体抗炎药可抑制DC表面ASICs的电生理功能,提示其如同阿米洛利,具有ASICs阻断剂的效应。据此,本实验应用非甾体抗炎药探讨细胞外酸化对DC表面抗原提呈相关分子表达的调控作用与ASICs的关系。
培养7天的DC用非甾体抗炎药布洛芬或双氯芬酸(均为200μM)预处理30 min(37℃,5%CO2),然后在pH6.5培养基培养4h(37℃,7%CO2),流式细胞术检测表面分子CD11c、MHCⅡ、CD80和CD86表达。结果显示：与对照组(pH6.5单独刺激4h)相比,布洛芬和双氯芬酸处理组的分子表达水平明显降低(n=6,p<0.05),提示细胞外酸化对DC表面抗原提呈相关分子表达的调控作用为ASICs依赖性。
结论
1. BMDC可表达功能性ASICs,后者参与细胞外酸化对DC表面抗原提呈相关分子表达的调控作用。
2.非甾体抗炎药可调控DC表面ASICs的电生理功能,并影响微环境酸化对DC表面抗原提呈相关分子表达的调节作用,提示ASICs可能是非甾体抗炎药发挥免疫抑制效应的新靶点。
pH value is an important physiological indicator of internal environment homeostasis. Under normal conditions, pH values in Peripheral blood, tissues and organs are usually 7.2-7.4. However, in some diseases, such as inflammation, autoimmune disease and tumors, the values of extracellular pH are much lower than that of normal tissues, and low pH values play an important role in developments of these diseases. Therefore, it is necessary to clarify the effects of extracellular pH on immune cells and their function.
As the most potent antigen-presentation cells (APCs) of the immune system, dendritic cells (DCs) are specialized to capture, process and present antigens to T lymphocytes to initiate Ag-specific T cell response. Some surface molecules of DCs are involved in the process of antigen presentation, such as MHC, costimulatory molecules CD80 and CD86. Many reports have showed that DCs play an important role in the developments of inflammatory diseases, tumors and autoimmune diseases. Although it has been reported that acidosis improves the uptake of antigens and MHC I-restricted presentation by DCs, the molecular mechanism through which DCs are regulated by acidosis has remained unknown.
Acid-sensing ion channels (ASICs) represent an H+-gated subgroup of the degenerin/epithelial Na+ channel (DEG/ENaC) family of cation channels and are activated by extracellular protons. They are widely expressed in peripheral sensory neurons and in the neurons of the central nervous system. ASICs are involved in nociception, mechanosensation, learning and memory and formation of sour taste. Recent studies have reported that ASICs are also expressed in non neuronal cells and have important effects on their physiological and pathological function.
We proposed that ASICs served as sensors for extracellular acidosis and mediate the responses of DCs to acidosis. In the present study, we investigated the expression of ASICs in mouse DCs and the role of ASICs in the effect of acidosis on DCs function.
1. ASICs are functional expressed in DCs
We first performed RT-PCR and western blot to detect the expression of ASIC1、ASIC2 and ASIC3 at mRNA and protein levels, respectively. As a result, mRNAs and proteins for all the three ASICs were detected in DCs. Furthermore, we used immunocytochemistry and electron microscope to determine cellular and subcellular distributions of ASICs in DCs. The results showed that ASIC1 and ASIC3 were expressed in endoplasmic reticulum and mitochondria, while ASIC2 existed in cell membrane.
To determine whether the expression of the ASIC proteins in DCs has function, we performed whole-cell patch clamp recordings. In the 85%(n=36/42) of the recorded DCs, the rapid drop of extracellular pH elicited inward ASICs-like currents, indicating the presence of functional ASIC channels. Usually, this transient inward current contained two phases:early fast and late slow inactivation. The mean amplitude of ASICs-like currents induced by pH 6.0 was 329.63±52.36 pA. The ASICs-like currents in DCs were reversibly inhibited by amiloride (100μM), a blocker of ASICs (n=6, P<0.05). The response of DCs to the drop of pH was in a dose-dependent manner. The threshold extracellular pH to elicit the inward current was about 7.0 and the maximum response appeared at 5.0. The extracellular pH producing 50% effect (pHso) was 6.08±0.05, and the Hill coefficient was 1.03±0.07 (n=6).
2. Acidosis induced the currents in DCs via ASICs
As a non-selective cation channel, TRPV1 also can evoke membrane currents at low extracellular pH (<6.0). Thereby, we examined the effect of Capsaicin (Cap), a selective agonist of TRPV1, on DCs with whole cell patch clamp technique. As a result,10μM Cap significantly evoked an inward current in cortex neurons. However,10μM Cap, even 100μM Cap failed to induce any inward currents in DCs. Moreover, we did not detect the TRPV1 mRNA expressing in DCs by PT-PCR. These results suggest that, the inward currents induced by decrease of extracellular pH are mediated by ASICs and not TRPV1 channels in DCs.
Previous studies have demonstrated that NSAIDs significantly inhibited ASICs currents in hippocampus and sensory neurons. To investigate the effect of NSAIDs on ASICs in DCs, we tested the responses of ASICs currents to NSAIDs, ibuprofen or diclofenac. Extracellular application of 200μM ibuprofen significantly reduced ASICs currents from 364.17±57.15 pA to 176.07±28.77 pA. The inhibitory percentage was 51.49±3.75% and the inhibition could be reversed by extensive washes with bath solution. Similarly, diclofenac (200μM) also significantly reduced ASICs currents from 353.97±51.58 pA to 166.7±18.57 pA. The inhibition was also reversible and the inhibitory percentage was 51.67±8.3%. These data suggested that ASICs currents in DCs are also sensitive to NSAIDs.
3. ASICs are involved in the up-regulation of surface molecules CD11c, MHCⅡ, CD80 and CD86 induced by acidosis in DCs
We incubated DCs in pH7.3 for 30 min at 37℃in the presence of amiloride (100μM), a blocker of ASICs, before exposuring to pH6.5 for 4 h at 37℃, and examined the MFI of surface molecules CD11c, MHCⅡ, CD80 and CD86 by flow cytometry. The up-regulations of CD11c, MHC classⅡ, CD80 and CD86 expressing stimulated by acidosis were significantly inhibited by amiloride, suggesting that ASICs are involved in up-regulation of surface molecules CD11c, MHCⅡ, CD80 and CD86 expressings in DCs induced by acidosis.
Since we have confirmed that NSAIDs can inhibit the function of ASICs in DCs, we next examined the effect of NASIDs on up-regulation of CD11c, MHCⅡ, CD80 and CD86 expressing in DCs induced by acidosis. DCs were pre-incubated with Ibuprofen (200μM) or Diclofenac (200μM) in pH7.3 for 30 min at 37℃, and then exposured to pH6.5 for 4 h. As a result, the expressings of CD11c, MHCⅡ, CD80 and CD86 were significantly lower than that of pH6.5 treated alone, indicating that NASIDs can inhibited the up-regulation of CD11c, MHCⅡ, CD80 and CD86 expressings induced by acidosis.
Conclusions
1. ASICs are functional expressed in DCs.
2. ASICs mediated the up-regulation of cell surface molecules CD11c, MHC classⅡ, CD80 and CD86 expressings induced by acidosis.
3. ASICs may be a new therapeutic target for regulating function of DCs in inflammation, tumors and autoimmune disease.
抗原提呈细胞(APC)重要的免疫系统组分,在固有免疫和适应性免疫应答中发挥重要作用。树突状细胞(DC)是体内最重要的的专职APC,负责摄取、加工和处理抗原,并将抗原信息提呈给初始T细胞,启动抗原特异性T细胞应答。已证明,DC表面多种膜分子参与抗原提呈过程：DC表面MHC分子与抗原肽结合为复合物(pMHC),将抗原肽提呈给T细胞(产生第一信号)；DC表面CD80或CD86与T细胞表面CD28结合,可提供T细胞激活的第二信号(共刺激信号)。此外,DC也参与多种免疫病理过程(如炎症、肿瘤和自身免疫病等)发生、发展。文献已报道,细胞微环境酸化可促进DC吞噬功能和抗原提呈(MHCⅠ类分子途径),但其确切机制尚不清楚。
酸敏感离子通道(ASICs, acid-sensing ion channels)是一类H+门控的阳离子通道,属上皮钠通道／退化蛋白[ENaC (epithelial sodium channel)/DEG (degenerin)]家族。ASICs主要表达于中枢和外周神经元,与触觉、学习记忆、痛觉和酸味觉形成有关。近年报道,非神经细胞(平滑肌细胞和骨细胞)和淋巴细胞(T细胞)也可表达ASICs,后者参与相关细胞的功能调控。
本研究以小鼠骨髓来源的DC为研究对象,拟探讨重要的专职APC-DC是否表达ASICs,在此基础上,观察微环境酸化对DC的功能调控作用及其与ASICs的关系。
一、DC表达功能性ASICs
1.DC表达ASICs
体外诱导BMDC分化,提取其总RNA和全蛋白,借助RT-PCR和Western blot证明：DC可表达ASIC1、ASIC2和ASIC3的mRNA和蛋白质。借助免疫荧光双标法和免疫电镜胶体金法检测ASIC在DC内的定位,结果显示：ASIC1和ASIC3分别表达于DC内质网和线粒体,细胞膜未见表达；而ASIC2主要表达于胞膜。
2.DC表面ASICs的电生理功能
借助全细胞膜片钳检测DC所表达ASICs的电生理功能,结果显示：细胞外pH6.0可激活DC胞膜表面ASICs样内向电流,该电流包含早期快速激活和晚期慢速失活两个时相,且能被ASICs阻断剂阿米洛利可逆性阻断(n=6,p<0.05)。pH6.0激活的ASICs样电流具有如下特点：平均幅度为329.63±52.36 pA；该内向电流具有pH依赖性：激活电流的最大pH值在7.0左右,产生最大电流的pH值为5.0；pH50为6.08±0.05,Hill系数为1.03±0.07(n=6)。
二、细胞外酸化诱发的DC内向电流依赖于ASICs
1.细胞外酸化诱发的DC内向电流不依赖于TRPV1
瞬时受体电位香草酸亚型1(TRPV1, transient receptor potential vanilloid-1)亦称VR1,属非选择性阳离子通道。细胞外pH值低于6.0,可在细胞膜产生内向电流。以皮层神经元为阳性对照,TRPV1激动剂辣椒素不能诱发DC产生TRPV1电流,提示DC不表达功能性TRPV1。另外,借助RT-PCR也未能在DC检出TRPV1 mRNA表达。上述实验结果提示：细胞外pH值降低诱发DC所产生的电流并非TRPV1介导,其为ASICs依赖性(见前述)。
2.非甾体抗炎药抑制DC表面ASICs的电生理功能
文献报道,非甾体抗炎药可抑制海马和感觉神经元ASICs的功能。本研究借助全细胞膜片钳技术,观察非甾体抗炎药(布洛芬和双氯芬酸)对DC表面ASICs电生理功能的影响。结果显示：布洛芬(200μM)和双氯芬酸(200μM)均可明显降低DC的ASICs电流(前者从364.17±57.15 pA降低为176.07±28.77 pA,抑制率51.49±3.75%；后者从353.97±51.58 pA降低为166.7±18.57 pA,抑制率51.67±8.3%),该抑制效应为可逆性。上述结果提示,非甾体抗炎药可抑制DC表面ASICs的电生理功能。
三、细胞外酸化通过ASICs调控DC功能
1.细胞外酸化通过ASICs上调DC表面抗原提呈相关分子表达
用ASICs阻断剂阿米洛利(100μM)预处理培养7天的DC(30 min,37℃,5%CO2),然后在pH6.5的培养基中培养4 h(37℃,7%CO2),流式细胞术检测DC表面CD11c、MHCIⅡ、CD80和CD86表达。结果显示：与对照组(pH6.5单独刺激4 h)相比,阿米洛利可明显抑制DC表面相关分子表达(n=6,p<0.05),提示微环境酸化可通过ASICs而调控DC表面抗原提呈相关分子表达。
2.非甾体抗炎药通过抑制ASICs功能而影响细胞外酸化对DC表面抗原提呈相关分子表达的调控作用
前面实验结果已证实,非甾体抗炎药可抑制DC表面ASICs的电生理功能,提示其如同阿米洛利,具有ASICs阻断剂的效应。据此,本实验应用非甾体抗炎药探讨细胞外酸化对DC表面抗原提呈相关分子表达的调控作用与ASICs的关系。
培养7天的DC用非甾体抗炎药布洛芬或双氯芬酸(均为200μM)预处理30 min(37℃,5%CO2),然后在pH6.5培养基培养4h(37℃,7%CO2),流式细胞术检测表面分子CD11c、MHCⅡ、CD80和CD86表达。结果显示：与对照组(pH6.5单独刺激4h)相比,布洛芬和双氯芬酸处理组的分子表达水平明显降低(n=6,p<0.05),提示细胞外酸化对DC表面抗原提呈相关分子表达的调控作用为ASICs依赖性。
结论
1. BMDC可表达功能性ASICs,后者参与细胞外酸化对DC表面抗原提呈相关分子表达的调控作用。
2.非甾体抗炎药可调控DC表面ASICs的电生理功能,并影响微环境酸化对DC表面抗原提呈相关分子表达的调节作用,提示ASICs可能是非甾体抗炎药发挥免疫抑制效应的新靶点。
pH value is an important physiological indicator of internal environment homeostasis. Under normal conditions, pH values in Peripheral blood, tissues and organs are usually 7.2-7.4. However, in some diseases, such as inflammation, autoimmune disease and tumors, the values of extracellular pH are much lower than that of normal tissues, and low pH values play an important role in developments of these diseases. Therefore, it is necessary to clarify the effects of extracellular pH on immune cells and their function.
As the most potent antigen-presentation cells (APCs) of the immune system, dendritic cells (DCs) are specialized to capture, process and present antigens to T lymphocytes to initiate Ag-specific T cell response. Some surface molecules of DCs are involved in the process of antigen presentation, such as MHC, costimulatory molecules CD80 and CD86. Many reports have showed that DCs play an important role in the developments of inflammatory diseases, tumors and autoimmune diseases. Although it has been reported that acidosis improves the uptake of antigens and MHC I-restricted presentation by DCs, the molecular mechanism through which DCs are regulated by acidosis has remained unknown.
Acid-sensing ion channels (ASICs) represent an H+-gated subgroup of the degenerin/epithelial Na+ channel (DEG/ENaC) family of cation channels and are activated by extracellular protons. They are widely expressed in peripheral sensory neurons and in the neurons of the central nervous system. ASICs are involved in nociception, mechanosensation, learning and memory and formation of sour taste. Recent studies have reported that ASICs are also expressed in non neuronal cells and have important effects on their physiological and pathological function.
We proposed that ASICs served as sensors for extracellular acidosis and mediate the responses of DCs to acidosis. In the present study, we investigated the expression of ASICs in mouse DCs and the role of ASICs in the effect of acidosis on DCs function.
1. ASICs are functional expressed in DCs
We first performed RT-PCR and western blot to detect the expression of ASIC1、ASIC2 and ASIC3 at mRNA and protein levels, respectively. As a result, mRNAs and proteins for all the three ASICs were detected in DCs. Furthermore, we used immunocytochemistry and electron microscope to determine cellular and subcellular distributions of ASICs in DCs. The results showed that ASIC1 and ASIC3 were expressed in endoplasmic reticulum and mitochondria, while ASIC2 existed in cell membrane.
To determine whether the expression of the ASIC proteins in DCs has function, we performed whole-cell patch clamp recordings. In the 85%(n=36/42) of the recorded DCs, the rapid drop of extracellular pH elicited inward ASICs-like currents, indicating the presence of functional ASIC channels. Usually, this transient inward current contained two phases:early fast and late slow inactivation. The mean amplitude of ASICs-like currents induced by pH 6.0 was 329.63±52.36 pA. The ASICs-like currents in DCs were reversibly inhibited by amiloride (100μM), a blocker of ASICs (n=6, P<0.05). The response of DCs to the drop of pH was in a dose-dependent manner. The threshold extracellular pH to elicit the inward current was about 7.0 and the maximum response appeared at 5.0. The extracellular pH producing 50% effect (pHso) was 6.08±0.05, and the Hill coefficient was 1.03±0.07 (n=6).
2. Acidosis induced the currents in DCs via ASICs
As a non-selective cation channel, TRPV1 also can evoke membrane currents at low extracellular pH (<6.0). Thereby, we examined the effect of Capsaicin (Cap), a selective agonist of TRPV1, on DCs with whole cell patch clamp technique. As a result,10μM Cap significantly evoked an inward current in cortex neurons. However,10μM Cap, even 100μM Cap failed to induce any inward currents in DCs. Moreover, we did not detect the TRPV1 mRNA expressing in DCs by PT-PCR. These results suggest that, the inward currents induced by decrease of extracellular pH are mediated by ASICs and not TRPV1 channels in DCs.
Previous studies have demonstrated that NSAIDs significantly inhibited ASICs currents in hippocampus and sensory neurons. To investigate the effect of NSAIDs on ASICs in DCs, we tested the responses of ASICs currents to NSAIDs, ibuprofen or diclofenac. Extracellular application of 200μM ibuprofen significantly reduced ASICs currents from 364.17±57.15 pA to 176.07±28.77 pA. The inhibitory percentage was 51.49±3.75% and the inhibition could be reversed by extensive washes with bath solution. Similarly, diclofenac (200μM) also significantly reduced ASICs currents from 353.97±51.58 pA to 166.7±18.57 pA. The inhibition was also reversible and the inhibitory percentage was 51.67±8.3%. These data suggested that ASICs currents in DCs are also sensitive to NSAIDs.
3. ASICs are involved in the up-regulation of surface molecules CD11c, MHCⅡ, CD80 and CD86 induced by acidosis in DCs
We incubated DCs in pH7.3 for 30 min at 37℃in the presence of amiloride (100μM), a blocker of ASICs, before exposuring to pH6.5 for 4 h at 37℃, and examined the MFI of surface molecules CD11c, MHCⅡ, CD80 and CD86 by flow cytometry. The up-regulations of CD11c, MHC classⅡ, CD80 and CD86 expressing stimulated by acidosis were significantly inhibited by amiloride, suggesting that ASICs are involved in up-regulation of surface molecules CD11c, MHCⅡ, CD80 and CD86 expressings in DCs induced by acidosis.
Since we have confirmed that NSAIDs can inhibit the function of ASICs in DCs, we next examined the effect of NASIDs on up-regulation of CD11c, MHCⅡ, CD80 and CD86 expressing in DCs induced by acidosis. DCs were pre-incubated with Ibuprofen (200μM) or Diclofenac (200μM) in pH7.3 for 30 min at 37℃, and then exposured to pH6.5 for 4 h. As a result, the expressings of CD11c, MHCⅡ, CD80 and CD86 were significantly lower than that of pH6.5 treated alone, indicating that NASIDs can inhibited the up-regulation of CD11c, MHCⅡ, CD80 and CD86 expressings induced by acidosis.
Conclusions
1. ASICs are functional expressed in DCs.
2. ASICs mediated the up-regulation of cell surface molecules CD11c, MHC classⅡ, CD80 and CD86 expressings induced by acidosis.
3. ASICs may be a new therapeutic target for regulating function of DCs in inflammation, tumors and autoimmune disease.
引文
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