Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production.
The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1-3). As Ucp2 is widely expressed in mammalian tissues, uncouples respiration and resides within a region of genetic linkage to obesity, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages, suggesting a role for Ucp2 in immunity or inflammatory responsiveness. We investigated the response to infection with Toxoplasma gondii in Ucp2-/- mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2-/- mice (63% decrease, P<0.04). Macrophages from Ucp2-/- mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.
Arsenijevic
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Centre de Recherche de Hôpital Laval et Centre de Recherche sur le Métabolisme Energétique, Université Laval, Québec, Canada.
Onuma
H
H
Pecqueur
C
C
Raimbault
S
S
Manning
B S
BS
Miroux
B
B
Couplan
E
E
Alves-Guerra
M C
MC
Goubern
M
M
Surwit
R
R
Bouillaud
F
F
Richard
D
D
Collins
S
S
Ricquier
D
D
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D018390:Gene Targeting; D007109:Immunity / Q000235:genetics*; D007473:Ion Channels; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D011506:Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014124:Toxoplasmosis, Animal / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014475:Uncoupling Agents / Q000378:metabolism; D000071246:Uncoupling Protein 2
D017931:DNA Primers; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2