n-n-dimethylsphingenine and Reperfusion-Injury

Topics: Apoptosis; Cell Division; Cell Membrane; Hydrogen Bonding; Inflammation; Neoplasm Metastasis; Neoplasms; Platelet Activation; Protein Kinase C; Reperfusion Injury; Signal Transduction; Sphingolipids; Sphingosine

Regulatory T cells (Tregs) are key components of the peripheral tolerance system and have become an immunotherapeutic agent for treating inflammatory processes. This therapeutic option, however, is hampered by problems arising from isolating and expanding desirable Tregs. Here we used an alternative approach with a pharmacologic agent to stimulate Tregs to achieve immunosuppressive effects. Pretreatment of mice with the naturally occurring sphingosine N,N-dimethylsphingosine (DMS) was found to increase both tissue-infiltrating T effectors (Teffs, CD4(+)Foxp3(-)) and Tregs (CD4(+)Foxp3(+)) in the early phase of bilateral renal ischemia/reperfusion injury. DMS itself had no effects on renal function or histopathology, but rapidly and transiently increased both Teffs and Tregs and increased the expression of chemokines CXCL9, CCL5, and CXCL10 in non-ischemic kidneys (sham operation). This renoprotection was abolished by administration of the Treg suppressing agents, anti-CTLA-4 or anti-CD25 monoclonal antibodies, suggesting that Tregs play a key role in DMS-induced renoprotection. Thus, Tregs recruited to the kidney by DMS ameliorate acute kidney injury and provide a new approach to control inflammatory diseases.

Topics: Acute Kidney Injury; Animals; Antibodies, Monoclonal; Chemokine CCL5; Chemokine CXCL10; Chemokine CXCL9; Chemotaxis, Leukocyte; CTLA-4 Antigen; Cytoprotection; Disease Models, Animal; Enzyme Inhibitors; Forkhead Transcription Factors; Immunologic Factors; Interleukin-2 Receptor alpha Subunit; Ischemia; Kidney; Male; Mice; Phosphotransferases (Alcohol Group Acceptor); Reperfusion Injury; Sphingosine; T-Lymphocytes, Regulatory; Time Factors; Tumor Necrosis Factor-alpha

Lai and colleagues demonstrate that pretreatment with N,N-dimethylsphingosine (DMS), a naturally occurring sphingosine derivative, provides renoprotection in ischemia/reperfusion injury. This DMS-induced renoprotection was abolished by the administration of agents that suppress regulatory T cells (Tregs) or by anti-CTLA-4 or anti-CD45 monoclonal antibodies, suggesting that Tregs played a critical role. The finding that Tregs are recruited to the kidney via DMS points to the exciting potential of new approaches to harnessing Tregs for therapeutic purposes.

Topics: Acute Kidney Injury; Animals; Chemotaxis, Leukocyte; Immunologic Factors; Ischemia; Kidney; Male; Reperfusion Injury; Sphingosine; T-Lymphocytes, Regulatory