title: Non-classical proIL-1beta activation during mammary gland infection is pathogen-dependent but caspase-1 independent.
abstract: Infection of the mammary gland with live bacteria elicits a pathogen-specific host inflammatory response. To study these host-pathogen interactions wild type mice, NF-kappaB reporter mice as well as caspase-1 and IL-1beta knockout mice were intramammarily challenged with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). The murine mastitis model allowed to compare the kinetics of the induced cytokine protein profiles and their underlying pathways. In vivo and ex vivo imaging showed that E. coli rapidly induced NF-kappaB inflammatory signaling concomitant with high mammary levels of TNF-alpha, IL-1 alpha and MCP-1 as determined by multiplex analysis. In contrast, an equal number of S. aureus bacteria induced a low NF-kappaB activity concomitant with high mammary levels of the classical IL-1beta fragment. These quantitative and qualitative differences in local inflammatory mediators resulted in an earlier neutrophil influx and in a more extensive alveolar damage post-infection with E. coli compared to S. aureus. Western blot analysis revealed that the inactive proIL-1beta precursor was processed into pathogen-specific IL-1beta fragmentation patterns as confirmed with IL-1beta knockout animals. Additionally, caspase-1 knockout animals allowed to investigate whether IL-1beta maturation depended on the conventional inflammasome pathway. The lack of caspase-1 did not prevent extensive proIL-1beta fragmentation by either of S. aureus or E. coli. These non-classical IL-1beta patterns were likely caused by different proteases and suggest a sentinel function of IL-1beta during mammary gland infection. Thus, a key signaling nodule can be defined in the differential host innate immune defense upon E. coli versus S. aureus mammary gland infection, which is independent of caspase-1.
authors.affiliation: Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Breyne
authors.affiliation: Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Cool
authors.affiliation: Department of Medical Protein Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent University, Ghent, Belgium.
authors.forename: Dieter
authors.initials: D
authors.lastname: Demon
authors.affiliation: Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Demeyere
authors.affiliation: Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent University, Zwijnaarde, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Vandenberghe
authors.affiliation: Department for Molecular Biomedical Research, Vlaams Instituut voor Biotechnologie (VIB), Ghent University, Zwijnaarde, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Carlsen
authors.affiliation: Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Wim
authors.initials: W
authors.lastname: Van Den Broeck
authors.affiliation: Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Niek N
authors.initials: NN
authors.lastname: Sanders
authors.affiliation: Department of Pharmacology, Toxicology and Biochemistry, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Meyer
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D008321:Mammary Glands, Animal / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008413:Mastitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013045:Species Specificity; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D016328:NF-kappa B; D020170:Caspase 1