PMID- 34440821
OWN - NLM
STAT- MEDLINE
DCOM- 20211119
LR  - 20211119
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 8
DP  - 2021 Aug 10
TI  - The Cell-Permeable Derivative of the Immunoregulatory Metabolite Itaconate, 
      4-Octyl Itaconate, Is Anti-Fibrotic in Systemic Sclerosis.
LID - 10.3390/cells10082053 [doi]
LID - 2053
AB  - Systemic sclerosis (SSc) is an autoimmune connective tissue disease that leads to 
      skin fibrosis. Altered metabolism has recently been described in autoimmune 
      diseases and SSc. Itaconate is a product of the Krebs cycle intermediate 
      cis-aconitate and is an immunomodulator. This work examines the role of the 
      cell-permeable derivative of itaconate, 4-octyl itaconate (4-OI), in SSc. SSc and 
      healthy dermal fibroblasts were exposed to 4-OI. The levels of collagen 
      Nrf2-target genes and pro-inflammatory cytokines interleukin 6 (IL-6) and 
      monocyte chemotactic protein 1 (MCP-1) were determined. Levels of reactive oxygen 
      species (ROS) as well as the gene expression of collagen and Cellular 
      Communication Network Factor 2 (CCN2) were measured after transforming growth 
      factor beta 1 (TGF-beta1) stimulation in the presence or absence of 4-OI. Wild-type 
      or Nrf2-knockout (Nrf2-KO) mouse embryonic fibroblasts (MEFs) were also treated 
      with 4-OI to determine the role of Nrf2 in 4-OI-mediated effects. 4-OI reduced 
      the levels of collagen in SSc dermal fibroblasts. Incubation with 4-OI led to 
      activation of Nrf2 and its target genes heme oxygenase 1 (HO-1) and NAD(P)H 
      quinone oxidoreductase 1 (NQO1). 4-OI activated antioxidant response element 
      (ARE)-dependent gene expression, reduced inflammatory cytokine release and 
      reduced TGF-beta1-induced collagen and ROS production in dermal fibroblasts. The 
      effects of 4-OI are dependent on Nrf2. The cell-permeable derivative of itaconate 
      4-OI is anti-fibrotic through upregulation of Nrf2 and could be a potential 
      therapeutic option in an intractable disease.
FAU - Henderson, John
AU  - Henderson J
AD  - Applied Sciences, NorthuMbria University, Ellison Place, Newcastle Upon Tyne NE7 
      7XA, UK.
FAU - Dayalan Naidu, Sharadha
AU  - Dayalan Naidu S
AD  - Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK.
FAU - Dinkova-Kostova, Albena T
AU  - Dinkova-Kostova AT
AUID- ORCID: 0000-0003-0316-9859
AD  - Cellular Medicine, School of Medicine, University of Dundee, Dundee DD1 4HN, UK.
FAU - Przyborski, Stefan
AU  - Przyborski S
AD  - Biosciences, Durham University, South Road, Durham DH1 3LE, UK.
FAU - Stratton, Richard
AU  - Stratton R
AD  - Institute of Inflammation, University College London, Pond Street, London WC1E 
      6BT, UK.
FAU - O Reilly, Steven
AU  - O Reilly S
AD  - Biosciences, Durham University, South Road, Durham DH1 3LE, UK.
LA  - eng
PT  - Journal Article
DEP - 20210810
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (4-octyl itaconate)
RN  - 0 (Interleukin-6)
RN  - 0 (MIRN29 microRNA, mouse)
RN  - 0 (MicroRNAs)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Succinates)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 139568-91-5 (Connective Tissue Growth Factor)
RN  - 9007-34-5 (Collagen)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - EC 1.6.5.2 (NAD(P)H Dehydrogenase (Quinone))
RN  - EC 1.6.5.2 (Nqo1 protein, mouse)
RN  - Q4516562YH (itaconic acid)
SB  - IM
MH  - Animals
MH  - Antioxidant Response Elements/drug effects/genetics
MH  - Collagen/metabolism
MH  - Connective Tissue Growth Factor/metabolism
MH  - Down-Regulation/*drug effects
MH  - Fibroblasts/cytology/drug effects/metabolism
MH  - Heme Oxygenase-1/genetics/metabolism
MH  - Humans
MH  - Interleukin-6/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - MicroRNAs/genetics/metabolism
MH  - NAD(P)H Dehydrogenase (Quinone)/genetics/metabolism
MH  - NF-E2-Related Factor 2/deficiency/genetics
MH  - Reactive Oxygen Species/metabolism
MH  - Scleroderma, Systemic/metabolism/*pathology
MH  - Succinates/*pharmacology
MH  - Transforming Growth Factor beta1/pharmacology
MH  - Up-Regulation/*drug effects
PMC - PMC8393335
OTO - NOTNLM
OT  - Nrf2
OT  - fibrosis
OT  - itaconate
OT  - metabolism
OT  - systemic sclerosis
COIS- The authors declare no conflict of interest.
EDAT- 2021/08/28 06:00
MHDA- 2021/11/20 06:00
PMCR- 2021/08/10
CRDT- 2021/08/27 01:08
PHST- 2021/06/16 00:00 [received]
PHST- 2021/07/16 00:00 [revised]
PHST- 2021/08/06 00:00 [accepted]
PHST- 2021/08/27 01:08 [entrez]
PHST- 2021/08/28 06:00 [pubmed]
PHST- 2021/11/20 06:00 [medline]
PHST- 2021/08/10 00:00 [pmc-release]
AID - cells10082053 [pii]
AID - cells-10-02053 [pii]
AID - 10.3390/cells10082053 [doi]
PST - epublish
SO  - Cells. 2021 Aug 10;10(8):2053. doi: 10.3390/cells10082053.