Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

Perez, Joëlle; Dansou, Boris; Hervé, Roxane; Lévi, Charlène; Tamouza, Houda; Vandermeersch, Sophie; Demey-Thomas, Emmanuelle; Haymann, Jean‐Philippe; Zafrani, Lara; Klatzmann, David; Boissier, Marie‐Christophe; Letavernier, Emmanuel; Baud, Laurent

doi:10.4049/jimmunol.1500749

Cited by 21 publications

(27 citation statements)

References 52 publications

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“…4A). The increased extracellular calpain expression by hypoxia is interesting, which is consistent with previous observations that hypoxia up-regulates proteases (28,29,42) and that calpain can be effectively secreted to the extracellular milieu (43)(44)(45)(46)(47). Third, our data show that the calpain-insensitive hERG-EAGS5P mutant was resistant to hypoxic culture (Fig.…”

Section: Discussionsupporting

confidence: 92%

Hypoxia reduces mature hERG channels through calpain up‐regulation

Lamothe¹,

Song²,

Guo³

et al. 2017

FASEB j.

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Human -related gene () encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium current () potassium channel, which is important for cardiac repolarization. Impairment of hERG function is the primary cause of acquired long QT syndrome, which predisposes individuals to cardiac arrhythmias and sudden death. Patients with hypoxia due to conditions such as cardiac ischemia or obstructive sleep apnea display increased incidence of cardiac arrhythmias and sudden death. We sought to understand the mechanisms that underlie hypoxia-associated cardiac arrhythmias. Using cell biology and electrophysiologic techniques, we found that hypoxic culture of hERG-expressing human embryonic kidney (HEK) cells and neonatal rat cardiomyocytes reduced hERG current/ and mature ERG channel expression with a concomitant increase in calpain expression. Calpain was actively released into the extracellular milieu and degraded cell-surface hERG. In contrast to hERG, the ether-a-go-go (EAG) channel was not reduced by hypoxic culture. By making chimeric channels between hERG and EAG, we identified that hypoxia-induced calpain degraded hERG by targeting its extracellular S5-pore linker. The scorpion toxin BeKm-1, which is known to selectively bind to the S5-pore linker of hERG, prevented hypoxia-induced hERG reduction. Our data provide novel information about hypoxia-mediated hERG dysfunction and may have biological and clinical implications in hypoxia-associated diseases.-Lamothe, S. M., Song, W., Guo, J., Li, W., Yang, T., Baranchuk, A., Graham, C. H., Zhang, S. Hypoxia reduces mature hERG channels through calpain up-regulation.

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Section: Discussionsupporting

confidence: 92%

Hypoxia reduces mature hERG channels through calpain up‐regulation

Lamothe¹,

Song²,

Guo³

et al. 2017

FASEB j.

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“…As extracellular calpain 1 concentration in BALF supernatant was a poor prognostic factor, we investigated the mechanism of action of extracellular calpain 1. Recently, our team identified TLR2 as a target for extracellular calpain in human lymphocytes (19) Our findings suggest that Calpain 1 is secreted by cancer cells use the innate immune system to generate an inflammatory microenvironment supporting tumor growth.…”

Section: Discussionmentioning

confidence: 75%

“…This externalization could be linked to cell death, apoptosis or necrosis. It could involve either the formation of microparticles (33) or the passage through the cell membrane via channels, such as ABCA1 transporter (19). ATP-binding cassette (ABC) transporters are a family of transmembrane proteins that transport a wide range of substrates, including lipids and the surfactant through the biological membranes (34).…”

Section: High Soluble Fragment Of Tlr2 Is Associated With a Pro-inflamentioning

confidence: 99%

“…When externalized, they seem to promote inflammation resolution and tissue repair. For instance, externalized calpains activate anti-inflammatory cytokines (TGF-β) (17) and inhibit pro inflammatory proteins such as chemerins or IL-17 (18) (19). In addition, extracellular calpains participate in epithelium and endothelium regeneration after ischemic or inflammatory damage (16)(20) (21).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, extracellular calpains participate in epithelium and endothelium regeneration after ischemic or inflammatory damage (16)(20) (21). Recently, our team demonstrated that extracellular calpains also cleave Toll like receptor 2 (TLR2) on human and murine lymphocytes, thereby limiting IL-17 expression (19). Finally, no data on extracellular calpain are available in oncology.…”

Section: Introductionmentioning

confidence: 99%

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Calpain 1 in bronchoalveolar lavage fluid is associated with poor prognosis in lepidic predominant pulmonary adenocarcinoma

et al. 2019

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Calpain 1 is a pro inflammatory calcium-activated cysteine protease, which can be partly externalized. Extracellular calpains limit inflammatory processes and promote tissue repair, through cell proliferation and migration. Toll like receptor (TLR) 2 has been identified as a target of extracellular calpains in lymphocytes. The aim was to investigate the externalization of calpain 1 and the release of soluble TLR2 during tumor progression of pulmonary lepidic predominant adenocarcinoma (LPA). Extracellular calpain 1, soluble fragment of TLR2 and cytokines were analyzed by ELISA in bronchoalveolar lavage fluid (BALF) supernatants from patients with LPA (n=68). Source of calpain was analyzed by immunohistochemistry and soluble TLR2 by flow cytometry on polymorphonuclear neutrophils (PMN) and human lung cancer cell lines. Extracellular calpain 1, secreted by tumor cells, was associated to tumor progression, neutrophilic inflammation, with a poor prognostic factor on survival (p=0.003). TLR2 was expressed on PMN and tumor cells and decreased after calpain exposure. Soluble fragment of TLR2 in BALF supernatants was correlated to the extracellular calpain 1 concentration (r=0.624; p<0.001), and its high level was associated with tumor progression and a proinflammatory environment. Extracellular calpain 1 secreted by tumor cells, could participate in inflammatory microenvironment and tumor progression through TLR2 in LPA.

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Targeting calpains: A novel immunomodulatory approach for microbial infections

Kumar

Ali

2017

European Journal of Pharmacology

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Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

Cited by 21 publications

References 52 publications

Hypoxia reduces mature hERG channels through calpain up‐regulation

Hypoxia reduces mature hERG channels through calpain up‐regulation

Calpain 1 in bronchoalveolar lavage fluid is associated with poor prognosis in lepidic predominant pulmonary adenocarcinoma

Targeting calpains: A novel immunomodulatory approach for microbial infections

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