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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autoimmune Diseases / immunology
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Autoimmune Diseases / pathology
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Autoimmune Diseases / prevention & control
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Bone Marrow Cells / immunology
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / pathology
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Humans
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Inflammation Mediators / antagonists & inhibitors
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Inflammation Mediators / metabolism
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Inflammation Mediators / physiology*
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Interleukin-1beta / antagonists & inhibitors
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Interleukin-1beta / biosynthesis*
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Interleukin-1beta / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Mutant Strains
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Neutrophils / immunology*
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Neutrophils / metabolism
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Neutrophils / pathology*
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Paracrine Communication / genetics
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Paracrine Communication / immunology
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / deficiency
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / physiology*
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Severity of Illness Index
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Signal Transduction / genetics
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Signal Transduction / immunology
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Skin Diseases / immunology
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Skin Diseases / pathology*
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Skin Diseases / prevention & control*
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Toll-Like Receptors / antagonists & inhibitors
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Toll-Like Receptors / physiology
Substances
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Inflammation Mediators
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Interleukin-1beta
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Toll-Like Receptors
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Ptpn6 protein, mouse