title: GPR91 deficiency exacerbates allergic contact dermatitis while reducing arthritic disease in mice.
abstract: BACKGROUND
  Succinate, in addition to its role as an intermediary of the citric acid cycle, acts as an alarmin, initiating and propagating danger signals resulting from tissue injury or inflammatory stimuli. The contribution of this immune sensing pathway to the development of allergic and inflammatory responses is unknown.
  
  
  METHODS
  Ear thickness of wild-type (wt) and Sucnr1-deficient (Sucnr1-/-) mice, sensitized and challenged with oxazolone, was used as a criterion to assess the relevance of SUCNR1/GPR91 expression mediating allergic contact dermatitis (ACD). Results obtained in this system were contrasted with data generated using passive cutaneous anaphylaxis, ovalbumin-induced asthma and arthritis models.
  
  
  RESULTS
  We found augmented ACD reactions in Sucnr1-/-mice. This observation correlated with increased mast cell activation in vitro and in vivo. However, exacerbated mast cell activation in Sucnr1-/-mice did not contribute to the enhancement of asthma or arthritis and seemed to be due to alterations during mast cell development as augmented mast cell responses could be recapitulated in wt mast cells differentiated in the absence of succinate.
  
  
  CONCLUSIONS
  A deficiency in succinate sensing during mast cell development confers these cells with a hyperactive phenotype. Such a phenomenon does not translate into exacerbation of asthma or mast cell-dependent arthritis. On the contrary, the fact that Sucnr1-/-mice developed reduced arthritic disease, using two different in vivo models, indicates that GPR91 antagonists may have therapeutic potential for the treatment of allergic and autoimmune diseases.
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.|Former NIBR, Vienna, Austria.
authors.forename: T
authors.initials: T
authors.lastname: Rubić-Schneider
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.|Former NIBR, Vienna, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Carballido-Perrig
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Regairaz
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Raad
authors.affiliation: Former NIBR, Vienna, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Jost
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Rauld
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: B
authors.initials: B
authors.lastname: Christen
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Wieczorek
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Kreutzer
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Dawson
authors.affiliation: Former NIBR, Vienna, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Lametschwandner
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Littlewood-Evans
authors.affiliation: Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland.|Former NIBR, Vienna, Austria.
authors.forename: J M
authors.initials: JM
authors.lastname: Carballido
mesh_terms: D000818:Animals; D001168:Arthritis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015415:Biomarkers; D016207:Cytokines / Q000378:metabolism; D017449:Dermatitis, Allergic Contact / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*
chemical_list: D015415:Biomarkers; D016207:Cytokines; C531499:GPR91 protein, mouse; D018836:Inflammation Mediators; D043562:Receptors, G-Protein-Coupled; D007073:Immunoglobulin E
keywords: alarmins; allergy; autoimmunity; immunometabolism; succinate