title: Neutrophils require SHP1 to regulate IL-1β production and prevent inflammatory skin disease.
abstract: The regulation of neutrophil recruitment, activation, and disposal is pivotal for circumscribed inflammation. SHP1(Y208N/Y208N) mutant mice develop severe cutaneous inflammatory disease that is IL-1R dependent. Genetic reduction in neutrophil numbers and neutrophilic responses to infection is sufficient to prevent the spontaneous initiation of this disease. Neutrophils from SHP1(Y208N/Y208N) mice display increased pro-IL-1β production due to altered responses to MyD88-dependent and MyD88-independent signals. The IL-1R-dependent inflammatory disease in SHP1(Y208N/Y208N) mice develops independently of caspase 1 and proteinase 3 and neutrophil elastase. In response to Fas ligand, a caspase 1-independent inducer of IL-1β production, neutrophils from SHP1(Y208N/Y208N) mice produce elevated levels of IL-1β but display reduced caspase 3 and caspase 7 activation. In neutrophils deficient in SHP1, IL-1β induces high levels of pro-IL-1β suggesting the presence of a paracrine IL-1β loop. These data indicate that the neutrophil- and IL-1-dependent disease in SHP1(Y208N/Y208N) mice is a consequence of loss of negative regulation of TLR and IL-1R signaling.
authors.affiliation: Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia. croker@wehi.edu.au
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.forename: Rowena S
authors.initials: RS
authors.lastname: Lewis
authors.forename: Jeff J
authors.initials: JJ
authors.lastname: Babon
authors.forename: Justine D
authors.initials: JD
authors.lastname: Mintern
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Zhang
authors.forename: Louise H
authors.initials: LH
authors.lastname: Cengia
authors.forename: Joanne A
authors.initials: JA
authors.lastname: O'Donnell
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication / Q000235:genetics / Q000276:immunology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D012871:Skin Diseases / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D051193:Toll-Like Receptors; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse