Galvanic current activates the NLRP3 inflammasome to promote type I collagen production in tendon
- Instituto Murciano de Investigación Biosanitaria, Spain
- University of Murcia, Spain
- MV Clinic, Spain
Abstract
The NLRP3 inflammasome coordinates inflammation in response to different pathogen- and damage-associated molecular patterns, being implicated in different infectious, chronic inflammatory, metabolic and degenerative diseases. In chronic tendinopathic lesions, different non-resolving mechanisms produce a degenerative condition that impairs tissue healing and which therefore complicates their clinical management. Percutaneous needle electrolysis consists of the application of a galvanic current and is an emerging treatment for tendinopathies. In the present study, we found that galvanic current activates the NLRP3 inflammasome and induces an inflammatory response that promotes a collagen-mediated regeneration of the tendon in mice. This study establishes the molecular mechanism of percutaneous electrolysis that can be used to treat chronic lesions and describes the beneficial effects of an induced inflammasome-related response.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 to 7.
Article and author information
Author details
Alejandro Peñin-Franch
Fermín Valera-Garrido
Funding
Ministerio de Ciencia, Innovación y Universidades (SAF2017‐88276‐R)
- Pablo Pelegrín
Ministerio de Ciencia, Innovación y Universidades (PID2020-116709RB-I00)
- Pablo Pelegrín
Fundación Séneca (20859/PI/18)
- Pablo Pelegrín
Fundación Séneca (21081/PDC/19)
- Pablo Pelegrín
European Research Council (614578)
- Pablo Pelegrín
European Research Concil (899636)
- Pablo Pelegrín
Ministerio de Ciencia, Innovación y Universidades (PID2020-113919RB-I00)
- Juan M Bueno
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Yousef Abu-Amer, Washington University School of Medicine, United States
Ethics
Animal experimentation: All experimental protocols for animal handling were refined and approved by the local animal research ethical committee (references 241/2016 and 541/2019) and Animal Health Service of the General Directorate of Fishing and Farming of the Council of Murcia (Servicio de Sanidad Animal, Dirección General de Ganadería y Pesca, Consejería de Agricultura y Agua de la Región de Murcia, reference A13160702). Animal experimentation was performed in strict accordance with the Hospital Clínico Universitario Vírgen de la Arrixaca animal experimentation guidelines, and the Spanish national (RD 1201/2005 and Law 32/2007) and EU (86/609/EEC and 2010/63/EU) legislation.
Human subjects: We present non-invasive ultrasound scanning images from routinely clinical following from a single patient. The data is completely anonymised and from the normal clinical routine practice.
Version history
- Received: September 7, 2021
- Preprint posted: September 22, 2021 (view preprint)
- Accepted: February 23, 2022
- Accepted Manuscript published: February 24, 2022 (version 1)
- Version of Record published: March 4, 2022 (version 2)
Copyright
© 2022, Peñin-Franch et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Galvanic current activates the NLRP3 inflammasome to promote type I collagen production in tendon
eLife 11:e73675.
https://doi.org/10.7554/eLife.73675
Further reading
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- Immunology and Inflammation
- Medicine
Background:
Prinflammatory extracellular chromatin from neutrophil extracellular traps (NETs) and other cellular sources is found in COVID-19 patients and may promote pathology. We determined whether pulmonary administration of the endonuclease dornase alfa reduced systemic inflammation by clearing extracellular chromatin.
Methods:
Eligible patients were randomized (3:1) to the best available care including dexamethasone (R-BAC) or to BAC with twice-daily nebulized dornase alfa (R-BAC + DA) for seven days or until discharge. A 2:1 ratio of matched contemporary controls (CC-BAC) provided additional comparators. The primary endpoint was the improvement in C-reactive protein (CRP) over time, analyzed using a repeated-measures mixed model, adjusted for baseline factors.
Results:
We recruited 39 evaluable participants: 30 randomized to dornase alfa (R-BAC +DA), 9 randomized to BAC (R-BAC), and included 60 CC-BAC participants. Dornase alfa was well tolerated and reduced CRP by 33% compared to the combined BAC groups (T-BAC). Least squares (LS) mean post-dexamethasone CRP fell from 101.9 mg/L to 23.23 mg/L in R-BAC +DA participants versus a 99.5 mg/L to 34.82 mg/L reduction in the T-BAC group at 7 days; p=0.01. The anti-inflammatory effect of dornase alfa was further confirmed with subgroup and sensitivity analyses on randomised participants only, mitigating potential biases associated with the use of CC-BAC participants. Dornase alfa increased live discharge rates by 63% (HR 1.63, 95% CI 1.01–2.61, p=0.03), increased lymphocyte counts (LS mean: 1.08 vs 0.87, p=0.02) and reduced circulating cf-DNA and the coagulopathy marker D-dimer (LS mean: 570.78 vs 1656.96 μg/mL, p=0.004).
Conclusions:
Dornase alfa reduces pathogenic inflammation in COVID-19 pneumonia, demonstrating the benefit of cost-effective therapies that target extracellular chromatin.
Funding:
LifeArc, Breathing Matters, The Francis Crick Institute (CRUK, Medical Research Council, Wellcome Trust).
Clinical trial number:
-
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Trained immunity is the long-term functional reprogramming of innate immune cells, which results in altered responses toward a secondary challenge. Despite indoxyl sulfate (IS) being a potent stimulus associated with chronic kidney disease (CKD)-related inflammation, its impact on trained immunity has not been explored. Here, we demonstrate that IS induces trained immunity in monocytes via epigenetic and metabolic reprogramming, resulting in augmented cytokine production. Mechanistically, the aryl hydrocarbon receptor (AhR) contributes to IS-trained immunity by enhancing the expression of arachidonic acid (AA) metabolism-related genes such as arachidonate 5-lipoxygenase (ALOX5) and ALOX5 activating protein (ALOX5AP). Inhibition of AhR during IS training suppresses the induction of IS-trained immunity. Monocytes from end-stage renal disease (ESRD) patients have increased ALOX5 expression and after 6 days training, they exhibit enhanced TNF-α and IL-6 production to lipopolysaccharide (LPS). Furthermore, healthy control-derived monocytes trained with uremic sera from ESRD patients exhibit increased production of TNF-α and IL-6. Consistently, IS-trained mice and their splenic myeloid cells had increased production of TNF-α after in vivo and ex vivo LPS stimulation compared to that of control mice. These results provide insight into the role of IS in the induction of trained immunity, which is critical during inflammatory immune responses in CKD patients.
