Cross-Regulation of F-Box Protein FBXL2 with T-bet and TNF-α during Acute and Chronic Lung Allograft Rejection.
Cross-Regulation of F-Box Protein FBXL2 with T-bet and TNF-α during Acute and Chronic Lung Allograft Rejection.
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DOI：
10.4049/jimmunol.2200245
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发表时间：
2022-11-01
期刊：
影响因子：
--
通讯作者：
McDyer JF
中科院分区：
文献类型：
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作者：
Das A;Wang X;Wei J;Hoji A;Coon TA;Popescu I;Brown M;Frizzell S;Iasella CJ;Noda K;Sembrat JC;Devonshire K;Hannan SJ;Snyder ME;Pilewski JM;Sanchez PG;Chandra D;Mallampalli RK;Alder JK;Chen BB;McDyer JF
慢性肺移植功能障碍(CLAD)是肺移植受者长期存活的主要障碍。有证据支持1型同种异体免疫是急/慢性肺排斥反应的主要反应，但其免疫调节机制仍不完全清楚。我们研究了Fbox E3-连接酶系统、Fbxo3(促炎)和Fbxl2(抗炎；调节肿瘤坏死因子受体相关因子(TRAF)蛋白)的组合。使用小鼠原位肺移植模型，我们评估了BALB/c>；C57BL/6(急性排斥；第10天)的同种异体移植物，发现与同系移植物相比，Fbxo3显著诱导，Fbxl2蛋白减少，T-bet、干扰素-γ和TRAF蛋白1-5升高。在急性模型中，共刺激-阻断(mR1/CTLA4-Ig)治疗导致Fbxo3减弱，Fbx12保留，T-bet、干扰素-γ和TRAFs1-5显著降低，这与1型同种异体免疫的关键作用一致。免疫组织化学显示，与同种异体移植物或共刺激-阻断治疗的同种异体移植物相比，排斥期间呼吸道上皮细胞和浸润性单个核细胞中的Fbxo3：Fbxl2平衡发生了显著变化。在慢性肺排斥模型Dba/2J/C57BL/6F1>；Dba/2J(第28天)中，我们观察到持续升高的Fbxo3/Fbx12平衡和T-bet/干扰素-γ蛋白，以及与对照组相似的结果。我们假设Fbxl2调节T-bet，并在Jurkat细胞中发现Fbxl2足以使T-bet泛素化并与T-bet共免疫共沉淀，反之亦然。在MLE细胞中，Fbxl2以剂量依赖的方式抑制T-bet蛋白表达。在对1型细胞因子的检测中，发现肿瘤坏死因子-α对Fbxl2蛋白和基因表达水平有负性调节作用。综上所述，我们的研究结果表明，E3-连接酶Fbxo3/Fbx12系统通过Fbx12对T-bet起调节作用，在肺移植排斥反应中，肿瘤坏死因子-α对Fbxl2具有负交叉调节作用。
Chronic lung allograft dysfunction(CLAD) is the major barrier to long-term survival in lung transplant recipients(LTRs). Evidence supports Type-1 alloimmunity as the predominant response in acute/chronic lung rejection, the immunoregulatory mechanisms remain incompletely understood. We studied the combinatorial F box E3-ligase system, FBXO3(pro-inflammatory) and FBXL2(anti-inflammatory; regulates tumor necrosis factor receptor-associated factor(TRAF) protein). Using the mouse orthotopic lung transplant model, we evaluated allografts from BALB/c>C57BL/6(acute rejection; day-10) and found significant induction of FBXO3 and diminished FBXL2 protein along with elevated T-bet, IFN-γ and TRAF proteins 1–5 compared to isografts. In the acute model, treatment with costimulation-blockade (MR1/CTLA4-Ig)resulted in attenuated FBXO3, preserved FBXL2 and substantially reduced T-bet, IFN-γ and TRAFs 1–5, consistent with a key role for Type-1 alloimmunity. Immunohistochemistry revealed significant changes in the FBXO3:FBXL2 balance in airway epithelia and infiltrating mononuclear cells during rejection compared to isografts or costimulation-blockade-treated allografts. In the chronic lung rejection model, DBA/2J/C57BL/6F1>DBA/2J(day-28) we observed persistently elevated FBXO3/FBXL2 balance and T-bet/IFN-γ protein, and similar findings from LTR lungs with CLAD versus controls. We hypothesized that FBXL2 regulated T-bet and found FBXL2 was sufficient to polyubiquitinate T-bet and co-immunoprecipitated with T-bet on pull-down experiments and vice versa in Jurkat cells. Transfection with FBXL2 diminished T-bet protein in a dose-dependent manner in MLE cells. In testing Type-1 cytokines, TNF-α was found to negatively regulate FBXL2 protein and mRNA levels. Together, our findings show the combinatorial E3-ligase FBXO3/FBXL2 system plays a role in the regulation of T-bet through FBXL2, with negative cross-regulation of TNF-α on FBXL2 during lung allograft rejection.
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慢性肺同种异体移植功能障碍期间，1型免疫力和内源性免疫调节剂在气道转录组中占主导地位。
DOI：
10.1111/ajt.16360
发表时间：
2021-06
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Iasella CJ;Hoji A;Popescu I;Wei J;Snyder ME;Zhang Y;Xu W;Iouchmanov V;Koshy R;Brown M;Fung M;Langelier C;Lendermon EA;Dugger D;Shah R;Lee J;Johnson B;Golden J;Leard LE;Ellen Kleinhenz M;Kilaru S;Hays SR;Singer JP;Sanchez PG;Morrell MR;Pilewski JM;Greenland JR;Chen K;McDyer JF
通讯作者：
McDyer JF
影响因子：
4.4
作者：
Gelman, Andrew E.;Okazaki, Mikio;Kreisel, Daniel
通讯作者：
Kreisel, Daniel
影响因子：
6
作者：
Mimura, Takeshi;Walker, Natalie;Lama, Vibha N.
通讯作者：
Lama, Vibha N.
DOI：
10.1165/rcmb.2007-0257rc
发表时间：
2007-12-01
影响因子：
6.4
作者：
Okazaki, Mikio;Gelman, Andrew E.;Kreisel, Daniel
通讯作者：
Kreisel, Daniel
USP10 对 T-bet 的去泛素化和稳定化。
DOI：
10.1016/j.bbrc.2014.05.037
发表时间：
2014-07-04
影响因子：
3.1
作者：
Pan, Lina;Chen, Zuojia;Shi, Guochao
通讯作者：
Shi, Guochao