Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.
Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.
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DOI：
10.1016/j.clim.2016.05.011
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Mohan C
中科院分区：
文献类型：
--
作者：
Orme JJ;Du Y;Vanarsa K;Mayeux J;Li L;Mutwally A;Arriens C;Min S;Hutcheson J;Davis LS;Chong BF;Satterthwaite AB;Wu T;Mohan C
系统性红斑狼疮（SLE）的特点是抗体介导的慢性炎症在肾脏、肺、皮肤和其他器官引起炎症和损害。SLE中有几种炎症通路失调，了解这些通路可以改善诊断和治疗。在其中一个途径中，Axl酪氨酸激酶受体响应Gas6配体阻断白细胞炎症。可溶性Axl受体外结构域（sAxl）在SLE和狼疮易感小鼠的血清中升高。我们假设SLE血清中的sAxl起源于白细胞表面，白细胞Axl的缺失导致了疾病。我们确定巨噬细胞和B细胞是SLE和狼疮易感小鼠中sAxl的来源。基质金属蛋白酶ADAM10和TACE （ADAM17）介导了狼疮易感小鼠白细胞Axl外结构域的脱落。在体外研究中，狼疮易感巨噬细胞中Axl的缺失使其对gas6诱导的抗炎信号无反应。这种表型被ADAM10/TACE联合抑制所拯救。在肾炎诱导模型中，用抗肾小球基底膜（anti-GBM）血清刺激巨噬细胞缺陷的小鼠，其病情比对照组更严重。ADAM10和TACE也介导人SLE PBMC Axl的切割。总之，这些研究表明，增加的金属蛋白酶介导的白细胞Axl切割可能有助于狼疮的终末器官疾病。他们进一步建议双重抑制ADAM10/TACE作为SLE的潜在治疗方式。
Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE.
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DOI：
10.1152/ajpheart.00020.2004
发表时间：
2004-09-01
影响因子：
4.8
作者：
Hasanbasic, I;Cuerquis, J;Blostein, MD
通讯作者：
Blostein, MD
DOI：
10.1084/jem.20021553
发表时间：
2003-03-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bennett L;Palucka AK;Arce E;Cantrell V;Borvak J;Banchereau J;Pascual V
通讯作者：
Pascual V
影响因子：
8
作者：
Goruppi, S;Ruaro, E;Schneider, C
通讯作者：
Schneider, C
影响因子：
32.4
作者：
Chan, VWF;Meng, FY;Lowell, CA
通讯作者：
Lowell, CA
影响因子：
3.7
作者：
Abbas AR;Wolslegel K;Seshasayee D;Modrusan Z;Clark HF
通讯作者：
Clark HF