Cancer and Haematology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
J Immunol. 2011 Jan 15;186(2):1131-9. doi: 10.4049/jimmunol.1002702. Epub 2010 Dec 15.
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.
中性粒细胞募集、激活和清除的调节对于局限炎症至关重要。SHP1(Y208N/Y208N)突变小鼠发生严重的皮肤炎症性疾病，该疾病依赖于 IL-1R。中性粒细胞数量的遗传减少和对感染的中性粒细胞反应足以预防这种疾病的自发发作。由于对 MyD88 依赖性和非依赖性信号的反应改变，SHP1(Y208N/Y208N)小鼠的中性粒细胞显示出增加的前 IL-1β 产生。SHP1(Y208N/Y208N)小鼠的 IL-1R 依赖性炎症性疾病的发生独立于 caspase 1 和蛋白酶 3 和中性粒细胞弹性蛋白酶。在 Fas 配体（一种 caspase 1 非依赖性诱导 IL-1β 产生的物质）的刺激下，SHP1(Y208N/Y208N)小鼠的中性粒细胞产生高水平的 IL-1β，但显示出降低的 caspase 3 和 caspase 7 激活。在缺乏 SHP1 的中性粒细胞中，IL-1β 诱导高水平的前 IL-1β，表明存在旁分泌 IL-1β 环。这些数据表明，SHP1(Y208N/Y208N)小鼠中的中性粒细胞和 IL-1 依赖性疾病是 TLR 和 IL-1R 信号转导负调节丧失的后果。
