HuR modulation counteracts lipopolysaccharide response in murine macrophages.
Anti-inflammatory agents
ELAVL1
HuR
LPS
RIP-seq
Tanshinone mimics
Journal
Disease models & mechanisms
ISSN: 1754-8411
Titre abrégé: Dis Model Mech
Pays: England
ID NLM: 101483332
Informations de publication
Date de publication:
01 03 2023
01 03 2023
Historique:
received:
02
02
2023
accepted:
16
02
2023
medline:
30
3
2023
pubmed:
14
3
2023
entrez:
13
3
2023
Statut:
ppublish
Résumé
Lipopolysaccharide (LPS) exposure to macrophages induces an inflammatory response, which is regulated at the transcriptional and post-transcriptional levels. HuR (ELAVL1) is an RNA-binding protein that regulates cytokines and chemokines transcripts containing AU/U-rich elements (AREs) and mediates the LPS-induced response. Here, we show that small-molecule tanshinone mimics (TMs) inhibiting HuR-RNA interaction counteract LPS stimulus in macrophages. TMs exist in solution in keto-enolic tautomerism, and molecular dynamic calculations showed the ortho-quinone form inhibiting binding of HuR to mRNA targets. TM activity was lost in vitro by blocking the diphenolic reduced form as a diacetate, but resulted in prodrug-like activity in vivo. RNA and ribonucleoprotein immunoprecipitation sequencing revealed that LPS induces a strong coupling between differentially expressed genes and HuR-bound genes, and TMs reduced such interactions. TMs decreased the association of HuR with genes involved in chemotaxis and immune response, including Cxcl10, Il1b and Cd40, reducing their expression and protein secretion in primary murine bone marrow-derived macrophages and in an LPS-induced peritonitis model. Overall, TMs show anti-inflammatory properties in vivo and suggest HuR as a potential therapeutic target for inflammation-related diseases.
Identifiants
pubmed: 36912171
pii: 297137
doi: 10.1242/dmm.050120
pmc: PMC10110401
pii:
doi:
Substances chimiques
Lipopolysaccharides
0
ELAV-Like Protein 1
0
RNA
63231-63-0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : IG 21548
Organisme : Fondazione Pezcoller
Organisme : Associazione Italiana Contro le Leucemie - Linfomi e Mieloma
Organisme : H2020 Marie Skłodowska-Curie Actions
ID : 813239
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : 2017PHRC8X
Organisme : Università degli Studi di Trento
Informations de copyright
© 2023. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interests The authors declare no competing or financial interests.
Références
Autoimmun Rev. 2006 May;5(5):299-305
pubmed: 16782553
Arthritis Rheum. 2012 Jun;64(6):1730-9
pubmed: 22147649
Nucleic Acids Res. 2020 Jan 8;48(D1):D307-D313
pubmed: 31598693
J Cancer Prev. 2017 Dec;22(4):203-210
pubmed: 29302577
Inflamm Regen. 2019 Jun 6;39:12
pubmed: 31182982
Nat Rev Genet. 2021 Mar;22(3):185-198
pubmed: 33235359
EMBO J. 1998 Jun 15;17(12):3448-60
pubmed: 9628880
Eur J Pharmacol. 2006 Aug 7;542(1-3):1-7
pubmed: 16797002
J Comput Chem. 2004 Jul 15;25(9):1157-74
pubmed: 15116359
Nucleic Acids Res. 2019 Jan 25;47(2):1011-1029
pubmed: 30418581
Aging (Albany NY). 2010 Jun;2(6):333-43
pubmed: 20606251
Front Genet. 2019 Feb 04;10:31
pubmed: 30778370
Int Immunopharmacol. 2021 Aug;97:107819
pubmed: 34098486
Nat Immunol. 2010 Nov;11(11):973
pubmed: 20959797
Expert Rev Clin Immunol. 2010 Nov;6(6):831-41
pubmed: 20979548
J Chem Theory Comput. 2019 Jan 8;15(1):43-51
pubmed: 30512961
J Mol Graph. 1996 Feb;14(1):33-8, 27-8
pubmed: 8744570
J Comput Aided Mol Des. 2013 Mar;27(3):221-34
pubmed: 23579614
Sci Rep. 2018 May 31;8(1):8460
pubmed: 29855534
J Immunol Methods. 2000 Sep 21;243(1-2):243-55
pubmed: 10986418
Wiley Interdiscip Rev RNA. 2020 May;11(3):e1581
pubmed: 31970930
Arterioscler Thromb Vasc Biol. 2006 Dec;26(12):2622-9
pubmed: 16990552
J Chem Theory Comput. 2015 Aug 11;11(8):3696-713
pubmed: 26574453
Eur Respir J. 2005 Nov;26(5):933-47
pubmed: 16264057
J Comput Chem. 2009 Dec;30(16):2785-91
pubmed: 19399780
Mol Cell Biol. 2001 Sep;21(17):5889-98
pubmed: 11486028
Nat Immunol. 2018 Feb;19(2):120-129
pubmed: 29348497
J Phys Chem B. 2008 Jul 31;112(30):9020-41
pubmed: 18593145
SLAS Discov. 2019 Mar;24(3):314-331
pubmed: 30616427
Curr Opin Genet Dev. 2013 Feb;23(1):35-43
pubmed: 23312841
Phys Chem Chem Phys. 2020 Oct 15;22(39):22645-22661
pubmed: 33015693
BMC Mol Biol. 2013 Jul 09;14:15
pubmed: 23837869
Nat Chem Biol. 2007 Aug;3(8):508-15
pubmed: 17632515
Am J Physiol Heart Circ Physiol. 2002 Oct;283(4):H1497-504
pubmed: 12234802
J Immunol. 1998 Jul 15;161(2):927-32
pubmed: 9670971
J Immunol. 1985 Feb;134(2):982-9
pubmed: 2578168
Cancer Treat Rev. 2018 Feb;63:40-47
pubmed: 29207310
Inflammation. 2022 Feb;45(1):212-221
pubmed: 34467464
Nat Rev Drug Discov. 2018 Aug;17(8):559-587
pubmed: 29700501
J Cell Sci. 1998 Nov;111 ( Pt 21):3145-56
pubmed: 9763509
J Biol Chem. 1996 Apr 5;271(14):8144-51
pubmed: 8626503
Sci Rep. 2016 Mar 17;6:23240
pubmed: 26984741
J Comput Chem. 2020 Oct 5;41(26):2228-2239
pubmed: 32770577
Cell Cycle. 2007 Jun 1;6(11):1288-92
pubmed: 17534146
J Mater Chem B. 2018 Feb 28;6(8):1207-1215
pubmed: 32254181
Nat Immunol. 2014 Jun;15(6):492-502
pubmed: 24840980
Eur J Immunol. 2002 Jul;32(7):2037-45
pubmed: 12115625
Nat Protoc. 2006;1(1):302-7
pubmed: 17406249
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):18309-14
pubmed: 25422430
J Biol Chem. 1998 Mar 13;273(11):6417-23
pubmed: 9497373
J Biol Chem. 2008 Jul 4;283(27):19077-84
pubmed: 18463097
Nat Med. 2002 Dec;8(12):1414-20
pubmed: 12415259
Biotechniques. 2001 Apr;30(4):892-7
pubmed: 11314272
Bio Protoc. 2016 Dec 20;6(24):
pubmed: 28516119
Acta Crystallogr D Biol Crystallogr. 2013 Mar;69(Pt 3):373-80
pubmed: 23519412
Mol Syst Biol. 2016 May 13;12(5):868
pubmed: 27178967
Front Immunol. 2020 May 29;11:976
pubmed: 32547545
Blood. 2007 Apr 15;109(8):3308-15
pubmed: 17170125
Pharmacol Res. 2019 Apr;142:102-114
pubmed: 30794925
Nat Rev Immunol. 2010 Jan;10(1):24-35
pubmed: 20029446
J Comput Aided Mol Des. 2010 Jun;24(6-7):591-604
pubmed: 20354892
Curr Drug Targets. 2015;16(5):499-515
pubmed: 25706256
PLoS One. 2013 Aug 12;8(8):e72426
pubmed: 23951323
Trends Genet. 2008 Aug;24(8):416-25
pubmed: 18597886
Acta Crystallogr B. 2007 Apr;63(Pt 2):319-27
pubmed: 17374943
PLoS Genet. 2012 Sep;8(9):e1002977
pubmed: 23028373
J Chem Theory Comput. 2020 Oct 13;16(10):6007-6013
pubmed: 32955870
J Mol Biol. 2002 Jul 12;320(3):597-608
pubmed: 12096912
Glia. 2022 Jan;70(1):155-172
pubmed: 34533864
Immunity. 1999 Mar;10(3):387-98
pubmed: 10204494
J Comput Chem. 2005 Dec;26(16):1752-80
pubmed: 16211539
J Comput Aided Mol Des. 2007 Dec;21(12):681-91
pubmed: 17899391
J Med Chem. 2018 Feb 22;61(4):1483-1498
pubmed: 29313684
Arthritis Res Ther. 2014 Jun 17;16(3):R126
pubmed: 24939012
Nucleic Acids Res. 2017 Sep 19;45(16):9514-9527
pubmed: 28934484
Toxicol Appl Pharmacol. 2018 Apr 1;344:35-45
pubmed: 29496522
Adv Drug Deliv Rev. 2022 Feb;181:114088
pubmed: 34942276
J Chem Phys. 2007 Jan 7;126(1):014101
pubmed: 17212484
J Clin Invest. 2012 Jan;122(1):48-61
pubmed: 22201685
J Chem Theory Comput. 2011 Feb 8;7(2):525-37
pubmed: 26596171
Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):214-29
pubmed: 21935886
FEBS Lett. 2008 Jun 18;582(14):1977-86
pubmed: 18342629
Proteins. 2004 May 1;55(2):351-67
pubmed: 15048827
Sci Rep. 2015 Nov 10;5:16478
pubmed: 26553968
J Immunol. 2002 Jun 1;168(11):5885-92
pubmed: 12023393
Cancer Res. 2014 Sep 15;74(18):5322-35
pubmed: 25085247
Mol Cell. 2005 Sep 16;19(6):777-89
pubmed: 16168373