title: Toll-like receptor 4 regulates lipopolysaccharide-induced inflammation and lactation insufficiency in a mouse model of mastitis.
abstract: Lactation mastitis is a debilitating inflammatory breast disease in postpartum women. Disease severity is associated with markers of inflammation rather than bacterial load, suggesting that immune-signaling pathways activated in the host are important in the disease pathology. The role of the innate pattern recognition receptor toll-like receptor 4 (TLR4) in progression and resolution of mastitislike disease was investigated in a mouse model. Lipopolysaccharide in Matrigel (10 μg/10 μl) was administered into the teat canal of lactating Tlr4 null mutant and wild-type mice to induce a localized area of inflammation. Mastitis induction resulted in a marked influx of RB6-positive neutrophils and F4/80-positive macrophages, which was higher in Tlr4(-/-) mice compared to wild-type mice. Tlr4 null mutation resulted in an altered immune-signaling fingerprint following induction of mastitis, with attenuated serum cytokines, including CXCL1, CCL2, interleukin 1 beta, and tumor necrosis factor alpha compared to wild-type mice. In both genotypes, the localized area of inflammation had resolved after 7 days, and milk protein was evident. However, the mammary glands of wild-type mice exhibited reduced capacity for milk production, with decreased percent area populated with glandular epithelium and decreased abundance of nuclear phosphorylated signal transducer and activator of transcription 5 compared to Tlr4 null mice. This study demonstrates that inflammatory pathways activated in the host are critically important in mastitis disease progression and suggests that lactation insufficiency associated with mastitis may be a consequence of TLR4-mediated inflammation, rather than the bacterial infection itself.
authors.affiliation: School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Glynn
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hutchinson
authors.forename: Wendy V
authors.initials: WV
authors.lastname: Ingman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016009:Chi-Square Distribution; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005838:Genotype; D007113:Immunity, Innate / Q000276:immunology; D007150:Immunohistochemistry; D007774:Lactation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008413:Mastitis / Q000235:genetics / Q000276:immunology*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4
keywords: inflammation; lactation; mammary gland; mastitis; toll-like receptor