title: Uncoupling protein 2 negatively regulates mitochondrial reactive oxygen species generation and induces phosphatase-mediated anti-inflammatory response in experimental visceral leishmaniasis.
abstract: To reside and multiply successfully within the host macrophages, Leishmania parasites impair the generation of reactive oxygen species (ROS), which are a major host defense mechanism against any invading pathogen. Mitochondrial uncoupling proteins are associated with mitochondrial ROS generation, which is the major contributor of total cellular ROS generation. In the present study we have demonstrated that Leishmania donovani infection is associated with strong upregulation of uncoupling protein 2 (UCP2), a negative regulator of mitochondrial ROS generation located at the inner membrane of mitochondria. Functional knockdown of macrophage UCP2 by small interfering RNA-mediated silencing was associated with increased mitochondrial ROS generation, lower parasite survival, and induction of marked proinflammatory cytokine response. Induction of proinflammatory cytokine response in UCP2 knocked-down cells was a direct consequence of p38 and ERK1/2 MAPK activation, which resulted from ROS-mediated inhibition of protein tyrosine phosphatases (PTPs). Administration of ROS quencher, N-acetyl-l-cysteine, abrogated PTP inhibition in UCP2 knocked-down infected cells, implying a role of ROS in inactivating PTP. Short hairpin RNA-mediated in vivo silencing of UCP2 resulted in decreased Src homology 2 domain-containing tyrosine phosphatase 1 and PTP-1B activity and host-protective proinflammatory cytokine response resulting in effective parasite clearance. To our knowledge, this study, for the first time, reveals the induction of host UCP2 expression during Leishmania infection to downregulate mitochondrial ROS generation, thereby possibly preventing ROS-mediated PTP inactivation to suppress macrophage defense mechanisms.
authors.affiliation: Molecular Cell Biology Laboratory, Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata 700 032, India.
authors.forename: Writoban
authors.initials: W
authors.lastname: Basu Ball
authors.forename: Susanta
authors.initials: S
authors.lastname: Kar
authors.forename: Madhuchhanda
authors.initials: M
authors.lastname: Mukherjee
authors.forename: Ajit G
authors.initials: AG
authors.lastname: Chande
authors.forename: Robin
authors.initials: R
authors.lastname: Mukhopadhyaya
authors.forename: Pijush K
authors.initials: PK
authors.lastname: Das
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007893:Leishmania donovani / Q000276:immunology; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071246:Uncoupling Protein 2
chemical_list: D018836:Inflammation Mediators; D007473:Ion Channels; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D017027:Protein Tyrosine Phosphatases