ALX/FPR2 Modulates Anti-Inflammatory Responses in Mouse Submandibular Gland

• Published in: Scientific reports 2016-04, Vol.6 (1), p.24244, Article 24244
• Main Authors: Wang, Ching-Shuen, Wee, Yinshen, Yang, Chieh-Hsiang, Melvin, James E., Baker, Olga J.
• Format: Article
• Language: English
• Subjects: 14/19; 14/63; 38; 38/39; 38/77; 64; 64/60; 692/1807/1707; 692/420/256/2516; 692/699/255/1318; 82/1; 82/51; 82/80; Acetylcholine receptors (muscarinic); Animals; Apoptosis; Apoptosis - drug effects; Aquaporin 5; Aquaporin 5 - genetics; Aquaporin 5 - metabolism; Bacterial diseases; Cytokines; Cytokines - metabolism; Docosahexaenoic Acids - metabolism; Down-Regulation - drug effects; Exocrine glands; Female; Flow rates; Glands; Humanities and Social Sciences; Immunofluorescence; Inflammation; Inflammation - etiology; Inflammation - metabolism; Leukocytes - cytology; Leukocytes - drug effects; Leukocytes - immunology; Lipopolysaccharides; Lipopolysaccharides - toxicity; Lipoxin A4; Lipoxins - metabolism; Male; Mammalian cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Microscopy, Fluorescence; multidisciplinary; Polymerase chain reaction; Receptor, Muscarinic M3 - genetics; Receptor, Muscarinic M3 - metabolism; Receptors, Formyl Peptide - deficiency; Receptors, Formyl Peptide - genetics; Receptors, Formyl Peptide - metabolism; Rodents; Saliva; Salivary gland; Science; Structure-function relationships; Submandibular gland; Submandibular Gland - drug effects; Submandibular Gland - metabolism; Submandibular Gland - pathology; Tight Junctions - drug effects; Tight Junctions - metabolism; Tight Junctions - pathology; Up-Regulation - drug effects; Xerostomia; Xerostomia - etiology; Xerostomia - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep24244

Activation of the G-protein coupled formyl peptide receptor 2 (ALX/FPR2) by the lipid mediators lipoxin A 4 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.