TY - JOUR
T1 - Dysregulated anti-oxidant signalling and compromised mitochondrial integrity negatively influence regulatory T cell function and viability in liver disease
AU - Vaikunthanathan, Trishan
AU - Landmann, Emmanuelle
AU - Correa, Diana Marin
AU - Romano, Marco
AU - Trevelin, Silvia Cellone
AU - Peng, Qi
AU - Crespo, Elena
AU - Corrado, Mauro
AU - Lozano, Juan-José
AU - Pearce, Erika L.
AU - Perpinan, Elena
AU - Zoccarato, Anna
AU - Siew, Leonard
AU - Edwards-Hicks, Joy
AU - Khan, Reenam
AU - Luu, Nguyet-Thin
AU - Thursz, Mark R.
AU - Newsome, Philip N.
AU - Martinez-Llordella, Marc
AU - Shah, Naina
AU - Lechler, Robert I.
AU - Shah, Ajay M.
AU - Sanchez-Fueyo, Alberto
AU - Lombardi, Giovanna
AU - Safinia, Niloufar
PY - 2023/9
Y1 - 2023/9
N2 - Background
Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored.
Methods
The phenotypic and functional properties of CD4+CD25+CD127lo/- Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out.
Findings
Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera.
Interpretation
Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease.
Funding
This study was funded by the Wellcome Trust (211113/A/18/Z).
AB - Background
Dysregulated inflammatory responses and oxidative stress are key pathogenic drivers of chronic inflammatory diseases such as liver cirrhosis (LC). Regulatory T cells (Tregs) are essential to prevent excessive immune activation and maintain tissue homeostasis. While inflammatory cues are well known to modulate the function and stability of Tregs, the extent to which Tregs are influenced by oxidative stress has not been fully explored.
Methods
The phenotypic and functional properties of CD4+CD25+CD127lo/- Tregs isolated from patients with LC were compared to healthy controls (HC). Treg redox state was investigated by characterizing intracellular reactive oxygen species (ROS), NADPH oxidase-2 (Nox2) activity, mitochondrial function, morphology, and nuclear factor-erythroid 2-related factor (Nrf2) antioxidant signalling. The relevance of Nrf2 and its downstream target, Heme-oxygenase-1 (HO-1), in Treg function, stability, and survival, was further assessed using mouse models and CRISPR/Cas9-mediated HO-1 knock-out.
Findings
Circulating Tregs from LC patients displayed a reduced suppressive function, correlating with liver disease severity, associated with phenotypic abnormalities and increased apoptosis. Mechanistically, this was linked to a dysregulated Nrf2 signalling with resultant lower levels of HO-1, enhanced Nox2 activation, and impaired mitochondrial respiration and integrity. The functional deficit in LC Tregs could be partially recapitulated by culturing control Tregs in patient sera.
Interpretation
Our findings reveal that Tregs rely on functional redox homeostasis for their function, stability, and survival. Targeting Treg specific anti-oxidant pathways may have therapeutic potential to reverse the Treg impairment in conditions of oxidative damage such as advanced liver disease.
Funding
This study was funded by the Wellcome Trust (211113/A/18/Z).
U2 - 10.1016/j.ebiom.2023.104778
DO - 10.1016/j.ebiom.2023.104778
M3 - Article
SN - 2352-3964
VL - 95
JO - EBioMedicine
JF - EBioMedicine
M1 - 104778
ER -