title: ALX/FPR2 Modulates Anti-Inflammatory Responses in Mouse Submandibular Gland.
abstract: Activation of the G-protein coupled formyl peptide receptor 2 (ALX/FPR2) by the lipid mediators lipoxin A4 and resolvin D1 (RvD1) promotes resolution of inflammation. Our previous in vitro studies indicate that RvD1 activation of ALX/FPR2 resolves cytokine-mediated inflammatory responses in mammalian cells. However, the impact of ALX/FPR2 activation on salivary gland function in vivo is unknown. The objective of this study was to determine whether submandibular glands (SMG) from ALX/FPR2(-/-) mice display enhanced inflammatory responses to lipopolysaccharides (LPS) stimulation. For these studies, C57BL/6 and ALX/FPR2(-/-) mice at age 8-12-week-old were treated with LPS by i.p for 24 h. Salivary gland structure and function were analyzed by histopathological assessment, saliva flow rate, quantitative PCR, Western blot analyses and immunofluorescence. Our results showed the following events in the ALX/FPR2(-/-) mice treated with LPS: a) upregulated inflammatory cytokines and decreased M3R (Muscarinic Acetylcholine receptor M3) and AQP5 (Aquaporin 5) protein expression, b) decreased saliva secretion, c) increased apoptosis, d) alteration of tight junction and neuronal damage. Overall, our data suggest that the loss of ALX/FPR2 results in unresolved acute inflammation and SMG dysfunction (xerostomia) in response to LPS that is similar to human salivary gland dysfunction induced by bacterial infection.
authors.affiliation: School of Dentistry, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: Ching-Shuen
authors.initials: CS
authors.lastname: Wang
authors.affiliation: The Division of Microbiology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, 84102, USA.
authors.forename: Yinshen
authors.initials: Y
authors.lastname: Wee
authors.affiliation: Department of Bioengineering, University of Utah, Salt Lake City, Utah, 84112, USA.
authors.forename: Chieh-Hsiang
authors.initials: CH
authors.lastname: Yang
authors.affiliation: National Institute of Dental &Craniofacial Research, NIH, Bethesda, MD 20892, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Melvin
authors.affiliation: School of Dentistry, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: Olga J
authors.initials: OJ
authors.lastname: Baker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051402:Aquaporin 5 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000378:metabolism; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D044045:Lipoxins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013363:Submandibular Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D014987:Xerostomia / Q000209:etiology / Q000378:metabolism
chemical_list: D051402:Aquaporin 5; D016207:Cytokines; D008070:Lipopolysaccharides; D044045:Lipoxins; D043587:Receptor, Muscarinic M3; D044042:Receptors, Formyl Peptide; C481578:formyl peptide receptor 2, mouse; C040527:lipoxin A4; C518399:resolvin D1; D004281:Docosahexaenoic Acids