Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection

Watanabe‐Kusunoki, Kanako; Nakazawa, Daigo; Kusunoki, Yoshihiro; Kudo, Takashi; Hattanda, Fumihiko; Nishio, S.; Masuda, Sakiko; Tomaru, Utano; Kondo, Takeshi; Atsumi, Tatsuya; Ishizu, Akihiro

doi:10.1016/j.jaut.2019.102390

Cited by 16 publications

(19 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, recent reports have indicated that rTM acts as an immune modulator in addition to serving as an inflammatory regulator. In our study, rTM affected acquired immunity as well as neutrophil activation to resolve autoimmune vasculitis ( 15 ). Pathogenic ANCA auto-antibodies play a pivotal role in the development of ANCA-associated vasculitis.…”

Section: Experimental Evidence Of Rtm As An Immune Modulator Beyond Amentioning

confidence: 61%

“…These previous reports implied indirect effects against neutrophils. Recently, we ( 15 ) could show the direct effect of rTM binding to neutrophils, which inhibited auto-antibody-mediated NET formation. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, pathogenic myeloperoxidase (MPO)-ANCA binds to MPO expressed on tumor necrosis factor α-primed neutrophils, and the Fc region of ANCA crosslinks with the Fcγ receptor coupled with Mac-1 on neutrophils to activate spleen tyrosine kinase signaling and ROS production, which results in peptidylarginine deiminase 4 activation and NET formation ( 30 – 32 ).…”

Section: Nets and Tmmentioning

confidence: 95%

“…Ex vivo studies have shown that additional TMD1 binds to endothelial antigen during inflammation, competitively inhibiting leukocyte migration and adhesion ( 14 ). Furthermore, we ( 15 ) showed that recombinant TM (rTM), containing TMD123, directly binds to neutrophils via the macrophage-1 antigen (Mac-1) receptor, and thus inhibits neutrophil activation. In addition, rTM affects lymphocytes to inhibit pro-inflammatory cytokine/chemokine production during an inflammatory response.…”

Section: Anti-inflammatory Effects Of Tmmentioning

confidence: 99%

“…Although the efficacy of rTM has not been clinically shown in autoimmune disease and inflammatory disorder, several experimental data represent the potential to overcome these diseases. In vitro and animal studies indicate that rTM possesses the direct immunomodulatory effects in innate and acquired immunity independently of anti-coagulant effect ( 9 , 15 ). Based on animal studies ( Table 1A ), rTM is being clinically expected to contribute to resolving diseases with inflammation including diabetes mellitus, arthritis, bronchial asthma, and ischemic-reperfusion injury.…”

Section: Clinical Evidence For Rtm-based Strategiesmentioning

confidence: 99%

“…In particular, autoimmune ANCA vasculitis, which is characterized by immune dysregulation and intravascular injury, might be a candidate for rTM treatment. However, the dosage of rTM in many experimental situations ( 15 , 33 , 41 ) is 15–50 times of therapeutic dosage in patients with DIC and the effective concentration as an anti-inflammatory and immune-regulatory property remains unclear. Thus, in the future the indications of rTM therapy and the suitable dosage with no serious complications such as bleeding tendency should be carefully addressed.…”

Section: Clinical Evidence For Rtm-based Strategiesmentioning

confidence: 99%

See 4 more Smart Citations

Thrombomodulin as a Physiological Modulator of Intravascular Injury

et al. 2020

Self Cite

View full text Add to dashboard Cite

Thrombomodulin (TM), which is predominantly expressed on the endothelium, plays an important role in maintaining vascular homeostasis by regulating the coagulation system. Intravascular injury and inflammation are complicated physiological processes that are induced by injured endothelium-mediated pro-coagulant signaling, necrotic endothelialand blood cell-derived damage-associated molecular patterns (DAMPs), and DAMPmediated inflammation. During the hypercoagulable state after endothelial injury, TM is released into the intravascular space by proteolytic cleavage of the endothelium component. Recombinant TM (rTM) is clinically applied to patients with disseminated intravascular coagulation, resulting in protection from tissue injury. Recent studies have revealed that rTM functions as an inflammatory regulator beyond hemostasis through various molecular mechanisms. More specifically, rTM neutralizes DAMPs, including histones and high mobility group box 1 (HMGB1), suppresses excessive activation of the complement system, physiologically protects the endothelium, and influences both innate and acquired immunity. Neutrophil extracellular traps (NETs) promote immunothrombosis by orchestrating platelets to enclose infectious invaders as part of the innate immune system, but excessive immunothrombosis can cause intravascular injury. However, rTM can directly and indirectly regulate NET formation. Furthermore, rTM interacts with mediators of acquired immunity to resolve vascular inflammation. So far, rTM has shown good efficacy in suppressing inflammation in various experimental models, including thrombotic microangiopathy, sterile inflammatory disorders, autoimmune diseases, and sepsis. Thus, rTM has the potential to become a novel tool to regulate intravascular injury via pleiotropic effects.

show abstract

Section: Experimental Evidence Of Rtm As An Immune Modulator Beyond Amentioning

confidence: 61%

Section: Nets and Tmmentioning

confidence: 95%

Section: Anti-inflammatory Effects Of Tmmentioning

confidence: 99%

Section: Clinical Evidence For Rtm-based Strategiesmentioning

confidence: 99%

Section: Clinical Evidence For Rtm-based Strategiesmentioning

confidence: 99%

See 3 more Smart Citations

Thrombomodulin as a Physiological Modulator of Intravascular Injury

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase‐Positive Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Kudo

Nakazawa

Watanabe‐Kusunoki

et al. 2022

Arthritis & Rheumatology

Self Cite

View full text Add to dashboard Cite

Objective Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis, in which ANCA‐mediated neutrophil extracellular trap (NET) formation and subsequent endothelial cell necrosis occur. Cyclophilin D (CypD) plays an important role in mediation of cell necrosis and inflammation via the opening of mitochondrial permeability transition pores. This study was undertaken to examine the role of CypD in AAV pathogenesis. Methods We assessed the role and mechanism of CypD in ANCA‐stimulated neutrophils in vitro by immunostaining and electron microscopy observation. We performed a comprehensive RNA‐sequencing analysis on ANCA‐treated murine neutrophils. To investigate the role of CypD in vivo, we assessed disease features in CypD‐knockout mice and wild‐type mice using 2 different murine AAV models: anti‐myeloperoxidase IgG transfer–induced AAV and spontaneous AAV. Results In vitro experiments showed that pharmacologic and genetic inhibition of CypD suppressed ANCA‐induced NET formation via the suppression of reactive oxygen species and cytochrome c release from the mitochondria. RNA‐sequencing analyses in ANCA‐treated murine neutrophils revealed the involvement of inflammatory responses, with CypD deficiency reducing ANCA‐induced alterations in gene expression. Furthermore, analyses of upstream regulators revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that the CypD‐dependent opening of mitochondrial permeability transition pores is associated with ANCA‐induced neutrophil activation and NETosis. In both AAV mouse models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD‐dependent neutrophil and endothelial necrosis. Conclusion CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.

show abstract