title: Lpa2 is a negative regulator of both dendritic cell activation and murine models of allergic lung inflammation.
abstract: Negative regulation of innate immune responses is essential to prevent excess inflammation and tissue injury and promote homeostasis. Lysophosphatidic acid (LPA) is a pleiotropic lipid that regulates cell growth, migration, and activation and is constitutively produced at low levels in tissues and in serum. Extracellular LPA binds to specific G protein-coupled receptors, whose function in regulating innate or adaptive immune responses remains poorly understood. Of the classical LPA receptors belonging to the Edg family, lpa2 (edg4) is expressed by dendritic cells (DC) and other innate immune cells. In this article, we show that DC from lpa2(-/-) mice are hyperactive compared with their wild-type counterparts and are less susceptible to inhibition by different LPA species. In transient-transfection assays, we found that lpa2 overexpression inhibits NF-κB-driven gene transcription. Using an adoptive-transfer approach, we found that allergen-pulsed lpa2(-/-) DC induced substantially more lung inflammation than did wild-type DC after inhaled allergen challenge. Finally, lpa2(-/-) mice develop greater allergen-driven lung inflammation than do their wild-type counterparts in models of allergic asthma involving both systemic and mucosal sensitization. Taken together, these findings identify LPA acting via lpa2 as a novel negative regulatory pathway that inhibits DC activation and allergic airway inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Rochester Medical Center, Rochester, NY 14610, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Emo
authors.forename: Nida
authors.initials: N
authors.lastname: Meednu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Chapman
authors.forename: Fariba
authors.initials: F
authors.lastname: Rezaee
authors.forename: Marlene
authors.initials: M
authors.lastname: Balys
authors.forename: Troy
authors.initials: T
authors.lastname: Randall
authors.forename: Tirumalai
authors.initials: T
authors.lastname: Rangasamy
authors.forename: Steve N
authors.initials: SN
authors.lastname: Georas
mesh_terms: D000280:Administration, Inhalation; D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology*; D049368:Receptors, Lysophosphatidic Acid / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D000485:Allergens; D008246:Lysophospholipids; D016328:NF-kappa B; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid