IL-35 promotes CD4+Foxp3+ Tregs and inhibits atherosclerosis via maintaining CCR5-amplified Treg-suppressive mechanisms.
Animals
Aorta
/ metabolism
Atherosclerosis
/ genetics
CD4-Positive T-Lymphocytes
Cell Movement
Forkhead Transcription Factors
Interleukin-10
/ genetics
Interleukins
/ genetics
Mice
Mice, Knockout
Mice, Knockout, ApoE
Programmed Cell Death 1 Receptor
/ genetics
Proto-Oncogene Proteins c-akt
/ metabolism
Receptors, CCR5
/ genetics
Receptors, Immunologic
/ genetics
Signal Transduction
Spleen
/ metabolism
T-Lymphocytes, Regulatory
/ metabolism
TOR Serine-Threonine Kinases
/ metabolism
Atherosclerosis
Cardiology
Cellular immune response
Cytokines
Inflammation
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
08 10 2021
08 10 2021
Historique:
received:
21
06
2021
accepted:
20
08
2021
entrez:
8
10
2021
pubmed:
9
10
2021
medline:
16
3
2022
Statut:
epublish
Résumé
Tregs play vital roles in suppressing atherogenesis. Pathological conditions reshape Tregs and increase Treg-weakening plasticity. It remains unclear how Tregs preserve their function and how Tregs switch into alternative phenotypes in the environment of atherosclerosis. In this study, we observed a great induction of CD4+Foxp3+ Tregs in the spleen and aorta of ApoE-/- mice, accompanied by a significant increase of plasma IL-35 levels. To determine if IL-35 devotes its role in the rise of Tregs, we generated IL-35 subunit P35-deficient (IL-35P35-deficient) mice on an ApoE-/- background and found Treg reduction in the spleen and aorta compared with ApoE-/- controls. In addition, our RNA sequencing data show the elevation of a set of chemokine receptor transcripts in the ApoE-/- Tregs, and we have validated higher CCR5 expression in ApoE-/- Tregs in the presence of IL-35 than in the absence of IL-35. Furthermore, we observed that CCR5+ Tregs in ApoE-/- have lower Treg-weakening AKT-mTOR signaling, higher expression of inhibitory checkpoint receptors TIGIT and PD-1, and higher expression of IL-10 compared with WT CCR5+ Tregs. In conclusion, IL-35 counteracts hyperlipidemia in maintaining Treg-suppressive function by increasing 3 CCR5-amplified mechanisms, including Treg migration, inhibition of Treg weakening AKT-mTOR signaling, and promotion of TIGIT and PD-1 signaling.
Identifiants
pubmed: 34622804
pii: 152511
doi: 10.1172/jci.insight.152511
pmc: PMC8525592
doi:
pii:
Substances chimiques
CCR5 protein, mouse
0
Forkhead Transcription Factors
0
Foxp3 protein, mouse
0
IL10 protein, mouse
0
Interleukins
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Receptors, CCR5
0
Receptors, Immunologic
0
T cell Ig and ITIM domain protein, mouse
0
interleukin-35, mouse
0
Interleukin-10
130068-27-8
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL138749
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130233
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL131460
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK104116
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132399
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL147565
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK113775
Pays : United States
Références
Am J Pathol. 2003 Sep;163(3):1117-25
pubmed: 12937153
Nat Rev Immunol. 2012 Apr 20;12(5):325-38
pubmed: 22517423
Front Biosci. 2008 Jan 01;13:1472-99
pubmed: 17981643
Semin Immunol. 2009 Feb;21(1):14-21
pubmed: 18809338
Nat Rev Immunol. 2020 Nov;20(11):680-693
pubmed: 32269380
Front Biosci (Schol Ed). 2009 Jun 01;1:420-36
pubmed: 19482711
J Hepatol. 2016 Nov;65(5):944-952
pubmed: 27245433
Nature. 2020 Mar;579(7800):581-585
pubmed: 32103173
Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1734-41
pubmed: 27386935
J Immunol. 2003 Oct 1;171(7):3348-52
pubmed: 14500627
Nat Rev Immunol. 2008 Jul;8(7):523-32
pubmed: 18566595
Front Biosci (Landmark Ed). 2015 Jan 01;20:784-95
pubmed: 25553479
Blood. 2005 Dec 1;106(12):3846-53
pubmed: 16081683
J Hematol Oncol. 2014 Oct 31;7:80
pubmed: 25387998
Sci Transl Med. 2011 Nov 30;3(111):111ra120
pubmed: 22133721
Mediators Inflamm. 2019 Apr 10;2019:3152040
pubmed: 31093011
Cell Rep. 2020 Jan 14;30(2):481-496.e6
pubmed: 31940491
J Autoimmun. 2013 Mar;41:50-9
pubmed: 23490285
Nature. 2021 Mar;591(7851):652-658
pubmed: 33588426
Front Biosci (Landmark Ed). 2010 Jun 01;15:986-1006
pubmed: 20515737
Arterioscler Thromb Vasc Biol. 2020 Jun;40(6):e138-e152
pubmed: 32459541
J Neuroimmunol. 2016 Feb 15;291:59-69
pubmed: 26857496
Circ Res. 2016 May 13;118(10):1540-52
pubmed: 27021296
Mucosal Immunol. 2012 Mar;5(2):161-72
pubmed: 22236998
J Exp Med. 2008 Feb 18;205(2):339-46
pubmed: 18268038
Aging (Albany NY). 2020 Jan 4;12(1):193-203
pubmed: 31901899
Front Biosci (Landmark Ed). 2019 Nov 1;24:96-132
pubmed: 30468648
Cytokine. 2019 Oct;122:154076
pubmed: 28648331
J Cardiovasc Transl Res. 2016 Feb;9(1):49-66
pubmed: 26746407
Circ Res. 2016 Nov 11;119(11):1190-1203
pubmed: 27635087
Circulation. 2011 Jul 12;124(2):185-95
pubmed: 21690490
Immunity. 2007 Oct;27(4):635-46
pubmed: 17919943
Immunity. 2018 Nov 20;49(5):899-914.e6
pubmed: 30413360
Circ Res. 2016 May 13;118(10):1525-39
pubmed: 27006445
J Biol Chem. 2016 Mar 4;291(10):4939-54
pubmed: 26733204
Atherosclerosis. 2009 Apr;203(2):401-8
pubmed: 18789801
Eur J Immunol. 2001 Jul;31(7):2170-8
pubmed: 11449371
Cells. 2019 Feb 21;8(2):
pubmed: 30795546
Circulation. 2020 Sep 29;142(13):1279-1293
pubmed: 32703007
Hypertension. 2015 Apr;65(4):889-95
pubmed: 25601931
Blood. 2016 Aug 18;128(7):1013-7
pubmed: 27385791
Transplantation. 2006 Apr 15;81(7):1027-34
pubmed: 16612280
Front Biosci (Landmark Ed). 2016 Jan 1;21(1):70-88
pubmed: 26594106
Nutrients. 2019 Aug 07;11(8):
pubmed: 31394758
Int J Immunopathol Pharmacol. 2008 Oct-Dec;21(4):767-80
pubmed: 19144262
Open Biol. 2016 Jun;6(6):
pubmed: 27335323
Adv Exp Med Biol. 2009;665:90-105
pubmed: 20429418
Nat Med. 2006 Feb;12(2):178-80
pubmed: 16462800
Circulation. 2009 Nov 10;120(19):1893-902
pubmed: 19858416
J Immunol. 2010 Sep 15;185(6):3295-304
pubmed: 20720211
Immunity. 2014 Apr 17;40(4):569-81
pubmed: 24745333
Arterioscler Thromb Vasc Biol. 2019 Oct;39(10):2097-2119
pubmed: 31366217
JCI Insight. 2018 Jul 26;3(14):
pubmed: 30046006
Nat Med. 2014 Jun;20(6):633-41
pubmed: 24743305
Immunity. 2016 Nov 15;45(5):1122-1134
pubmed: 27851913
Nat Rev Cardiol. 2020 Jul;17(7):387-401
pubmed: 32203286
Immunity. 1996 May;4(5):471-81
pubmed: 8630732
Arterioscler Thromb Vasc Biol. 2018 Mar;38(3):599-609
pubmed: 29371247
Front Immunol. 2018 Jan 26;9:45
pubmed: 29434588
Oncogene. 2005 Jul 14;24(30):4778-88
pubmed: 15870695
J Hematol Oncol. 2013 Aug 22;6:61
pubmed: 23965413
Transl Res. 2015 Jan;165(1):221-40
pubmed: 25193380
J Clin Exp Cardiolog. 2012 Oct 8;2012(Suppl 12):2
pubmed: 23997979
Immunol Lett. 2020 Jun;222:58-66
pubmed: 32220615
Front Immunol. 2021 Feb 05;11:632239
pubmed: 33613572
Redox Biol. 2020 Jan;28:101373
pubmed: 31731100
Cancer Immunol Res. 2019 Jul;7(7):1175-1187
pubmed: 31160277
Drug Discov Today Ther Strateg. 2008;5(2):125-142
pubmed: 19578482
Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):893-900
pubmed: 17272749
Mol Med Rep. 2020 Jun;21(6):2522-2532
pubmed: 32323817
Cancer Immunol Immunother. 2011 Oct;60(10):1405-18
pubmed: 21638125
J Clin Invest. 2013 Mar;123(3):1323-34
pubmed: 23426179
PLoS One. 2012;7(3):e33628
pubmed: 22438968
J Immunol. 2018 Jul 15;201(2):481-492
pubmed: 29884702
J Clin Invest. 2015 Nov 2;125(11):4053-62
pubmed: 26413872
Nature. 2021 Mar;591(7849):300-305
pubmed: 33505023
Diabetes. 2014 Dec;63(12):4275-90
pubmed: 25008174
Mol Cancer. 2019 Nov 6;18(1):155
pubmed: 31690319
Cancer Res. 2018 Sep 15;78(18):5191-5199
pubmed: 30181177
J Cardiovasc Transl Res. 2016 Apr;9(2):135-44
pubmed: 26928596
J Biol Chem. 2015 Jul 31;290(31):19307-18
pubmed: 26085094
J Exp Med. 2014 Aug 25;211(9):1807-19
pubmed: 25073792
Blood. 2005 Nov 1;106(9):3068-73
pubmed: 16020508
Circ Res. 2016 Nov 11;119(11):1226-1241
pubmed: 27992360
Circ Res. 2005 Oct 28;97(9):922-7
pubmed: 16179587
Front Immunol. 2018 Oct 17;9:2374
pubmed: 30386337
Immunity. 2016 May 17;44(5):989-1004
pubmed: 27192565
Oncogenesis. 2018 Jan 24;7(1):10
pubmed: 29362402
Front Biosci. 2008 May 01;13:7143-55
pubmed: 18508723
Eur J Immunol. 2012 Jan;42(1):27-34
pubmed: 22161814
Nat Immunol. 2018 Mar;19(3):291-301
pubmed: 29434354
Antioxid Redox Signal. 2018 Apr 1;28(10):973-986
pubmed: 28325059
PLoS One. 2011;6(11):e27038
pubmed: 22073248
Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13445-50
pubmed: 19651619
J Neuroinflammation. 2016 Jul 20;13(1):223
pubmed: 27439902
Breast Cancer Res. 2011 Apr 26;13(2):R47
pubmed: 21521526
Circ Res. 2012 Jun 22;111(1):37-49
pubmed: 22628578
Burns Trauma. 2015 Dec;3(1):
pubmed: 26623425
Front Biosci. 2008 May 01;13:3986-4001
pubmed: 18508492
J Leukoc Biol. 2018 Jan 22;:
pubmed: 29357116
J Clin Immunol. 2006 Jan;26(1):1-6
pubmed: 16418797
Mol Cell Biol. 2013 Oct;33(20):4106-15
pubmed: 23979593
Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):804-16
pubmed: 25705917
Cell Rep. 2018 Oct 2;25(1):19-28.e5
pubmed: 30282028
Front Biosci (Landmark Ed). 2018 Jan 1;23:348-387
pubmed: 28930551
Circ Res. 2019 Jan 18;124(2):315-327
pubmed: 30653442
Front Immunol. 2020 Oct 14;11:595813
pubmed: 33154757
J Reprod Immunol. 2018 Feb;125:106
pubmed: 29406209
Nature. 2007 Nov 22;450(7169):566-9
pubmed: 18033300
Ann Oncol. 2018 Jan 1;29(1):71-83
pubmed: 29069302
Immunol Rev. 2017 Mar;276(1):97-111
pubmed: 28258697
Circ Res. 2016 Feb 19;118(4):620-36
pubmed: 26892962