Redox regulation of immunity and the role of small molecular weight thiols

Ghezzi, Pietro

doi:10.1016/j.redox.2021.102001

Cited by 9 publications

(7 citation statements)

References 134 publications

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“…The function of NNT is primarily to sustain mitochondrial antioxidant capacity through the generation of NADPH, which supports the antioxidant capacity of the glutathione and thioredoxin systems ( McCambridge et al, 2019 ; Meimaridou et al, 2018 ; Ronchi et al, 2013 ; Rydström, 2006 ; Ward et al, 2020 ). These systems are generally viewed as having broad anti-inflammatory activities ( Ghezzi, 2021 ; Yodoi et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Rawle

Dumenil

et al. 2022

eLife

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Granzyme A (GZMA) is a serine protease secreted by cytotoxic lymphocytes, with Gzma-/- mouse studies having informed our understanding of GZMA’s physiological function. We show herein that Gzma-/- mice have a mixed C57BL/6J and C57BL/6N genetic background and retain the full-length nicotinamide nucleotide transhydrogenase (Nnt) gene, whereas Nnt is truncated in C57BL/6J mice. Chikungunya viral arthritis was substantially ameliorated in Gzma-/- mice; however, the presence of Nnt and the C57BL/6N background, rather than loss of GZMA expression, was responsible for this phenotype. A new CRISPR active site mutant C57BL/6J GzmaS211A mouse provided the first insights into GZMA’s bioactivity free of background issues, with circulating proteolytically active GZMA promoting immune-stimulating and pro-inflammatory signatures. Remarkably, k-mer mining of the Sequence Read Archive illustrated that ≈27% of Run Accessions and ≈38% of BioProjects listing C57BL/6J as the mouse strain had Nnt sequencing reads inconsistent with a C57BL/6J genetic background. Nnt and C57BL/6N background issues have clearly complicated our understanding of GZMA and may similarly have influenced studies across a broad range of fields.

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Section: Resultsmentioning

confidence: 99%

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Rawle

Dumenil

et al. 2022

eLife

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“…Studies have shown that GSH depletion can promote apoptosis of CD4+ T lymphocytes and influence CD4+ T-cell proliferation via the mTOR pathway by increasing the expression of ROS 30 , 38 , 39 . GSH depletion promotes the release of pro-inflammatory cytokines in LPS-induced epithelial cells 36 , 40 . In contrast, GSH depletion regulates the adaptive immune response by inhibiting the secretion of IL-12 and IL-27 and disrupting the expression of surface molecules in BMDCs 23 , 41 .…”

Section: Discussionmentioning

confidence: 99%

“…Glutathione, a major component of the antioxidant defense system of living cells, is present in both prokaryotes and eukaryotes. GSH and oxidative stress are thought to play a key role in immunity, including autoimmunity [35][36][37]. Studies have shown that GSH depletion can promote apoptosis of CD4+ T lymphocytes and influence CD4+ T-cell proliferation via the mTOR pathway by increasing the expression of ROS [30,38,39].…”

Section: Discussionmentioning

confidence: 99%

Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling

Hu¹,

Zhang²,

Yi³

et al. 2022

Int. J. Biol. Sci.

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Dendritic cells (DCs) are the major antigen-presenting cells and play an important role in autoimmune uveitis. Emerging evidence suggests that bile acids (BAs) regulate DCs maturation. However, the underlying mechanisms by which BAs regulate the function of DCs still need to be clarified. Here, we demonstrate that lithocholic acid (LCA) inhibits the production of pro-inflammatory cytokines and the expression of surface molecules in bone marrow-derived dendritic cells (BMDCs). LCA attenuates the severity of EAU by modulating the maturation of splenic CD11C + MHCII high DCs. Notably, Takeda G-protein coupled receptor 5 (TGR5) deficiency partially reverses the inhibitory effect of LCA on DCs in vitro and in vivo . TGR5 activation also downregulates the NF-κB and MAPK pathways by inhibiting glutathione production and inducing oxidative stress in DCs, which leads to apoptosis and autophagy in DCs. In addition, LCA or INT-777 treatment increases the TGR5 expression in monocyte-derived dendritic cells (MD-DCs) of patients with active BD, whereas both LCA and TGR5 agonists inhibit the activation of MD-DCs. These results suggest that LCA and TGR5 agonists might be potential therapeutic drugs for the treatment of autoimmune uveitis.

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“…Interestingly, contradictory results have also been observed [ 185 , 186 ]. Therefore, the single use of NAC does not appear to be a sufficient treatment regime in the mouse model [ 187 ]. The organoselenium compound ebselen, under development for therapy of a variety of clinical conditions involving oxidative stress, reacts with GSH in a cyclic mechanism similar to that of GPx, thereby inactivating hydroperoxides, including H 2 O 2 and regenerating GSH [ 188 , 189 , 190 ].…”

Section: Methodsmentioning

confidence: 99%

Antioxidants as Therapeutic Agents in Acute Respiratory Distress Syndrome (ARDS) Treatment—From Mice to Men

et al. 2022

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Acute respiratory distress syndrome (ARDS) is a major cause of patient mortality in intensive care units (ICUs) worldwide. Considering that no causative treatment but only symptomatic care is available, it is obvious that there is a high unmet medical need for a new therapeutic concept. One reason for a missing etiologic therapy strategy is the multifactorial origin of ARDS, which leads to a large heterogeneity of patients. This review summarizes the various kinds of ARDS onset with a special focus on the role of reactive oxygen species (ROS), which are generally linked to ARDS development and progression. Taking a closer look at the data which already have been established in mouse models, this review finally proposes the translation of these results on successful antioxidant use in a personalized approach to the ICU patient as a potential adjuvant to standard ARDS treatment.

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Redox regulation of immunity and the role of small molecular weight thiols

Cited by 9 publications

References 134 publications

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies

Lithocholic acid inhibits dendritic cell activation by reducing intracellular glutathione via TGR5 signaling

Antioxidants as Therapeutic Agents in Acute Respiratory Distress Syndrome (ARDS) Treatment—From Mice to Men

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