Ecto-enzyme CD38: Regulator of dendritic cell migration

胞外酶 CD38：树突状细胞迁移的调节剂

• 批准号: 7039137
• 负责人: Frances E. Lund
• 金额: $ 34.18万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039137
• 关键词: CD38 molecule; T lymphocyte; biological signal transduction; cell migration; chemoattractants; chemokine receptor; chemotaxis; dendritic cells; flow cytometry; genetically modified animals; immune response; inflammation; laboratory mouse; ligands; neutrophil

DESCRIPTION (provided by applicant): Immune responses are dependent on the coordinated movement of leukocytes from sites of antigen deposition, to secondary lymphoid organs and to sites of infection or inflammation. Chemokines play a critical role in this process by directing leukocyte trafficking throughout the body. Although it is well known that leukocytes express chemokine receptors and can migrate directionally in response to chemokine gradients, the molecular mechanism(s) that control chemokine receptor responses are still largely unknown. CD38, an ADP-ribosyl cyclase, that catalyzes the production of the calcium-mobilizing metabolite cyclic ADP-ribose (cADPR), appears to be a critical regulator of chemokine receptor signaling and leukocyte trafficking. We observed that neutrophil migration is impaired in CD38-deficientmice resulting in attenuated and reduced inflammatory responses. We also found that the cADPPR produced byCD38 modulates calcium mobilization in neutrophils that have been activated with inflammatory chemoattractants such as peptides derived from bacteria and viruses. Furthermore, we showed that cADPR-specific antagonists block the migratory response of neutrophils to these peptides. The data suggest that small molecule inhibitors of CD38could potentially be used to block neutrophil-dependent inflammatory responses. Recently, we observed that the migratory response of dendritic cells is also impaired in CD38 deficient mice. Specifically, we found that CD38-deficient dendritic cells cannot migrate in response to ELC or SLC, chemokines that direct dendritic cells to migrate from sites of damage or injury to lymphoid tissues. This impaired chemotactic response observed inCD38-deficient dendritic cells results in inefficient T cell priming and significantly reduced T cell-dependent immune responses. Based on our previous data, we now hypothesize that CD38, through its production of cADPR, regulates cell-dependent immune responses by modulating the migration of dendritic cells. To test this hypothesis we have proposed the following Specific Aims: (1) we will determine whether CD38 regulates migration of all mature dendritic cell subsets to ELC or SLC, (2) we will determine whether CD38 regulates the migration of dendritic cells to inflammatory chemoattractants and (3) we will determine whether cADPR production by CD38 controls dendritic cell trafficking in vivo. These experiments will validate whether CD38 antagonists have the potential to be used as immunosuppressive agents that attenuate immune responses by modulating leukocyte trafficking.

描述（由申请人提供）：免疫反应取决于白细胞从抗原沉积部位，次级淋巴机构以及感染或炎症部位的协调运动。趋化因子在这一过程中通过指导整个体内的白细胞运输来发挥关键作用。尽管众所周知，白细胞表达趋化因子受体并可以响应趋化因子梯度迁移，但控制趋化因子受体反应的分子机制仍然在很大程度上未知。 CD38是一种ADP-核糖基环化酶，它催化钙溶剂化的代谢物环状ADP-核糖（CADPR）的产生似乎是趋化因子受体信号传导和白细胞运输的关键调节剂。我们观察到CD38缺乏症中嗜中性粒细胞迁移受损，导致炎症反应减弱和减少。我们还发现，CADPPR产生的BYCD38调节钙在中性粒细胞中的钙动员已被炎性趋化剂（例如源自细菌和病毒的肽）激活的中性粒细胞。此外，我们表明CADPR特异性拮抗剂阻止了中性粒细胞对这些肽的迁移反应。数据表明，CD38的小分子抑制剂可能可能用于阻断中性粒细胞依赖性炎症反应。最近，我们观察到CD38缺乏小鼠的树突状细胞的迁移反应也受损。具体而言，我们发现CD38缺陷的树突状细胞不能响应ELC或SLC迁移，这将导致树突状细胞从损伤或损伤部位迁移到淋巴组织组织。这种受损的趋化反应观察到INCD38缺陷的树突状细胞导致T细胞启动效率低下，并显着降低了T细胞依赖性免疫反应。基于我们以前的数据，我们现在假设CD38通过其生产CADPR来调节细胞依赖性免疫反应，通过调节树突状细胞的迁移。 To test this hypothesis we have proposed the following Specific Aims: (1) we will determine whether CD38 regulates migration of all mature dendritic cell subsets to ELC or SLC, (2) we will determine whether CD38 regulates the migration of dendritic cells to inflammatory chemoattractants and (3) we will determine whether cADPR production by CD38 controls dendritic cell tr​​afficking in vivo.这些实验将验证CD38拮抗剂是否有可能用作免疫抑制剂，从而通过调节白细胞运输来减轻免疫反应。

项目成果

Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes.

• DOI: 10.1084/jem.20071267
• 发表时间: 2007-10-29
• 期刊: The Journal of experimental medicine
• 作者: Shi G;Partida-Sánchez S;Misra RS;Tighe M;Borchers MT;Lee JJ;Simon MI;Lund FE
• 通讯作者: Lund FE

CD62L(neg)CD38⁺ expression on circulating CD4⁺ T cells identifies mucosally differentiated cells in protein fed mice and in human celiac disease patients and controls.

• DOI: 10.1038/ajg.2011.24
• 发表时间: 2011-06
• 期刊: AMERICAN JOURNAL OF GASTROENTEROLOGY
• 影响因子: 9.8
• 作者: du Pre, M. Fleur;van Berkel, Lisette A.;Raki, Melinda;van Leeuwen, Marieke A.;de Ruiter, Lilian F.;Broere, Femke;ter Borg, Mariette N. D.;Lund, Frances E.;Escher, Johanna C.;Lundin, Knut E. A.;Sollid, Ludvig M.;Kraal, Georg;Nieuwenhuis, Edward E. S.;Samsom, Janneke N.
• 通讯作者: Samsom, Janneke N.

Dual role of CD38 in microglial activation and activation-induced cell death.

• DOI: 10.4049/jimmunol.181.1.92
• 发表时间: 2008-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Mayo L;Jacob-Hirsch J;Amariglio N;Rechavi G;Moutin MJ;Lund FE;Stein R
• 通讯作者: Stein R

Redesign of Schistosoma mansoni NAD+ catabolizing enzyme: active site H103W mutation restores ADP-ribosyl cyclase activity.

曼氏血吸虫NAD分解代谢酶的重新设计：活性位点H103W突变恢复ADP-核糖基环化酶活性。

• DOI: 10.1021/bi060930g
• 发表时间: 2006
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Kuhn,Isabelle;Kellenberger,Esther;Rognan,Didier;Lund,FrancesE;Muller-Steffner,Hélène;Schuber,Francis
• 通讯作者: Schuber,Francis