Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement and SLE disease activity

Zhang, Mingjiao; Jie, Hongyu; Wu, Yong; Han, Xinai; Li, Xing; He, Yi; Shi, Xingliang; Luo, Yu-Long; Sun, Ying; Yang, Jinlong; Yang, Jing; Quan, Shulv; Lao, Xiaobin; Tan, Liping; Sun, Erwei

doi:10.21203/rs.3.rs-28049/v2

Cited by 3 publications

(3 citation statements)

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“…Overactivated necroptosis has been reported in many types of diseases affecting the tissue, including ischemia-reperfusion injury, neurodegenerative diseases, and inflammation (8). Intriguingly, necroptosis has also recently been found to be dysregulated in autoimmune diseases (23)(24)(25)(26), suggesting that necroptosis plays a vital role in autoimmune diseases by controlling the fate of a variety of cells.…”

Section: Discussionmentioning

confidence: 99%

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

Peng

Zhang

Liang

et al. 2022

Arthritis & Rheumatology

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Objective Myofiber necrosis is a significant pathologic characteristic of idiopathic inflammatory myopathies (IIMs), and its molecular mechanism is largely unknown. Necroptosis is a recently identified form of regulated necrotic cell death, and its activation might have crucial biologic consequences. The aim of the present study was to investigate the role of necroptosis in IIM muscle damage. Methods Western blot and immunohistochemistry analyses were performed to examine the expression of receptor‐interacting protein 3 (RIP‐3) and mixed‐lineage kinase domain–like (MLKL) proteins in 26 IIM patients and 4 healthy controls, as well as necroptosis‐related damage–associated molecular pattern molecules. Tumor necrosis factor (TNF) was used to stimulate cultured C2C12 myoblasts, and the involvement of necroptosis in cell death of C2C12 cells was studied in vitro. Results The expression of RIP‐3 and MLKL proteins and their phosphorylated forms was significantly increased in the muscle tissue of IIM patients compared to that of healthy controls. The expression levels of RIP‐3 and MLKL proteins were associated with the severity of muscle damage in patients with IIM. Significant colocalization of MLKL with high mobility group box chromosomal protein 1 in necrotizing myofibers was observed in muscle biopsy tissue from patients with IIM. Stimulation of C2C12 myoblasts with TNF and a pan‐caspase inhibitor, Z‐VAD, resulted in the overactivation of necroptosis and significantly increased necrotic cell death. Strategies involving either inhibition of necroptosis with necrostatin‐1 or knockdown of MLKL expression successfully prevented necroptosis‐induced cell death of C2C12 cells. Conclusion These findings demonstrate that overactivated necroptosis contributes to muscle damage in IIMs and suggest that necroptosis inhibitors could represent a new therapeutic target in the treatment of IIMs.

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Section: Discussionmentioning

confidence: 99%

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

Peng

Zhang

Liang

et al. 2022

Arthritis & Rheumatology

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“…BAFF is a type II transmembrane protein encoded by human chromosome 13q34, which is mainly expressed in peripheral blood mononuclear cells, lymph nodes, spleen, and thymus, but lowly expressed in the small intestine, pancreas, placenta, and lung [10,11]. Abundant evidence demonstrated that BAFF is involved in pathogenesis of systemic lupus erythematosus (SLE), which is a prototype autoimmune disease affecting multiple organ systems [12][13][14][15][16][17][18]. In these patients, a large number of autoantibodies are produced and the deposition of immune complexes occurs in multiple organs, especially in kidneys [19][20][21][22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Distinct binding mode of BAFF antagonist antibodies belimumab and tabalumab, analyzed by computer simulation

Sun¹,

Wei²

2022

J Mol Model

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B-cell activating factor (BAFF) can binding to specific receptors and activate signaling pathways associated with B cell activation. Belimumab and tabalumab are anti-BAFF monoclonal antibodies, while belimumab was proved by FDA in 2011 as a targeted therapy for systemic lupus erythematosus (SLE) and showed better clinical effect than tabalumab. The combination modes of BAFF-belimumab complex and BAFF-tabalumab complex were simulated to better understand the reason for the difference of the inhibition effect between belimumab and tabalumab. The structures of belimumab and tabalumab were constructed by homology modeling.The combination mode of BAFF-belimumab complex was analyzed by molecular dynamics simulation, and the combination mode of BAFF-tabalumab complex was analyzed by protein-protein docking after molecular dynamics simulation. Both belimumab and tabalumab contacted with BAFF at the same hydrophobic center which the natural receptors of BAFF bind to. I51, F54, K58 D100, D101, L102, L103, P105 of belimumab heavy chain and R27, Y30, K49, S65 of belimumab light chain contribute to the BAFF-belimumab interaction mainly by hydrogen bond, salt bridge and hydrophobic effect. More important, Belimumab could contact with L83 of BAFF and produced a steric hindrance with the adjacent BAFF trimers, while tabalumab could not. Belimumab had better clinical effect than tabalumab mainly because it could bind to L83 of BAFF and affect the formation of BAFF 60-mer, in addition to inhibition of the interaction of BAFF with its receptors.

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Section: Introductionmentioning

confidence: 99%

Distinct Binding Mode of BAFF antagonist antibodies Belimumab and Tabalumab, analyzed by computer simulation

Sun

Wei

2021

Preprint

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B-cell activating factor (BAFF) can binding to specific receptors and activate signaling pathways associated with B cell activation. Belimumab and tabalumab are anti-BAFF monoclonal antibodies, while belimumab was proved by FDA in 2011 as a targeted therapy for systemic lupus erythematosus (SLE) and showed better clinical effect than tabalumab. The combination modes of BAFF-belimumab complex and BAFF-tabalumab complex were simulated to better understand the reason for the difference of the inhibition effect between belimumab and tabalumab. The structures of belimumab and tabalumab were constructed by homology modeling. The combination mode of BAFF-belimumab complex was analyzed by molecular dynamics simulation, and the combination mode of BAFF-tabalumab complex was analyzed by protein-protein docking after molecular dynamics simulation. Both belimumab and tabalumab contacted with BAFF at the same hydrophobic center which the natural receptors of BAFF bind to. I51, F54, K58 D100, D101, L102, L103, P105 of belimumab heavy chain and R27, Y30, K49, S65 of belimumab light chain contribute to the BAFF-belimumab interaction mainly by hydrogen bond, salt bridge and hydrophobic effect. More important, Belimumab could contact with L83 of BAFF and produced a steric hindrance with the adjacent BAFF trimers, while tabalumab could not. Belimumab had better clinical effect than tabalumab mainly because it could bind to L83 of BAFF and affect the formation of BAFF 60-mer, in addition to inhibition of the interaction of BAFF with its receptors.

show abstract

Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement and SLE disease activity

Cited by 3 publications

References 24 publications

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

Contribution of Necroptosis to Myofiber Death in Idiopathic Inflammatory Myopathies

Distinct binding mode of BAFF antagonist antibodies belimumab and tabalumab, analyzed by computer simulation

Distinct Binding Mode of BAFF antagonist antibodies Belimumab and Tabalumab, analyzed by computer simulation

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