title: Neutrophil apoptosis in autoimmune Fas-defective MRL lpr/lpr mice.
abstract: The apoptosis-defective lpr (fas) mutation in MRL mice causes the early onset of a lupus-like autoimmune disease with concomitant inflammation. In order to analyse the consequences of the impaired Fas-dependent apoptosis on inflammation, the susceptibility to apoptosis of polymorphonuclear leukocytes (PMN), obtained from MRL lpr/lpr mice, has been studied. Peritoneal PMN from lpr/lpr and control (+/+) mice were recruited with a mild inflammatory stimulus. The number of cells collected from the peritoneal cavity of young lpr/lpr mice was comparable to that obtained from age-matched control mice, indicating that PMN homeostasis is maintained regardless of the loss-of-function Fas mutation. Recruited neutrophils were exposed in culture to apoptosis-inducing stimuli. Treatment with agonist anti-Fas antibody increased apoptosis of +/+ PMN, but did not affect lpr/lpr PMN which do not express Fas on their surface. However, lpr/lpr PMN could undergo both spontaneous and stimulus-induced apoptosis in a fashion comparable to or higher than that of control +/+ mice. Analysis of mRNA expression revealed that lpr/lpr PMN have reduced expression of IL-18, whereas IL-1beta, IFNgamma, caspase 1 and caspase 3 are expressed at levels comparable to those of +/+ cells. However, caspase-3-like activity was higher in PMN from lpr/lpr mice than in +/+ cells, and correlated with enhanced apoptosis. It could be concluded that in young, uncompromised lpr/lpr mice, PMN homeostasis is still fully regulated through the involvement of Fas-independent, compensatory, apoptotic mechanisms. This could include an increased participation of caspase 3 in the apoptotic pathway, consequent to enhanced activation of the enzyme and to the decreased production of IL-18, which acts as a competitive caspase 3 substrate.
authors.affiliation: Research Centre Dompé S.p.A., Via Campo di Pile, I-67100 L'Aquila, Italy.
authors.forename: E D
authors.initials: ED
authors.lastname: Giudice
authors.forename: A
authors.initials: A
authors.lastname: Ciaramella
authors.forename: N
authors.initials: N
authors.lastname: Balestro
authors.forename: D
authors.initials: D
authors.lastname: Neumann
authors.forename: P G
authors.initials: PG
authors.lastname: Romano
authors.forename: M P
authors.initials: MP
authors.lastname: Cesaroni
authors.forename: G
authors.initials: G
authors.lastname: Maurizi
authors.forename: P
authors.initials: P
authors.lastname: Ruggiero
authors.forename: D
authors.initials: D
authors.lastname: Boraschi
authors.forename: P
authors.initials: P
authors.lastname: Bossù
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001202:Ascitic Fluid / Q000166:cytology; D015551:Autoimmunity / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D019463:Mice, Inbred MRL lpr / Q000502:physiology*; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D002518:Ceramides; D016207:Cytokines; D019014:fas Receptor; D020169:Caspases