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Zusammenfassung:
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-1 beta 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-1 beta production, neutrophils from SHP1(Y208N/Y208N) mice produce elevated levels of IL-1 beta but display reduced caspase 3 and caspase 7 activation. In neutrophils deficient in SHP1, IL-1 beta induces high levels of pro-IL-1 beta suggesting the presence of a paracrine IL-1 beta 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. The Journal of Immunology, 2011, 186: 1131-1139.
