CARD9 negatively regulates NLRP3-induced IL-1β production on Salmonella infection of macrophages.
Interleukin-1β (IL-1β) is a proinflammatory cytokine required for host control of bacterial infections, and its production must be tightly regulated to prevent excessive inflammation. Here we show that caspase recruitment domain-containing protein 9 (CARD9), a protein associated with induction of proinflammatory cytokines by fungi, has a negative role on IL-1β production during bacterial infection. Specifically, in response to activation of the nucleotide oligomerization domain receptor pyrin-domain containing protein 3 (NLRP3) by Salmonella infection, CARD9 negatively regulates IL-1β by fine-tuning pro-IL-1β expression, spleen tyrosine kinase (SYK)-mediated NLRP3 activation and repressing inflammasome-associated caspase-8 activity. CARD9 is suppressed during Salmonella enterica serovar Typhimurium infection, facilitating increased IL-1β production. CARD9 is, therefore, a central signalling hub that coordinates a pathogen-specific host inflammatory response.
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
Milton
http://orcid.org/0000-0003-2977-1565
M
Pereira
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
Panagiotis
P
Tourlomousis
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
John
http://orcid.org/0000-0002-9758-9944
J
Wright
Medical Research Council Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge CB1 9NL, UK.
Tom
http://orcid.org/0000-0003-4097-1680
T
P Monie
Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge CB3 0ES, UK.
Clare E
CE
Bryant
Nature. 2009 May 21;459(7245):433-6
19339971
Nat Genet. 2014 Nov;46(11):1187-96
25305756
J Leukoc Biol. 2015 May;97(5):825-835
25605870
Proc Natl Acad Sci U S A. 2014 May 20;111(20):7403-8
24803432
Proc Natl Acad Sci U S A. 2014 May 20;111(20):7385-90
24799700
Annu Rev Immunol. 2011;29:707-35
21219188
Nucleic Acids Res. 2001 May 1;29(9):e45
11328886
Gastroenterology. 2012 Dec;143(6):1530-43
22967725
Nat Immunol. 2004 Aug;5(8):800-8
15220916
Nucleic Acids Res. 2010 Jan;38(Database issue):D792-9
19906719
Cell Death Differ. 2013 Sep;20(9):1149-60
23645208
Sci Rep. 2015 Jul 08;5:12018
26153766
J Exp Med. 2010 Aug 2;207(8):1745-55
20603313
Nat Immunol. 2007 Jun;8(6):619-29
17486093
PLoS Genet. 2013;9(9):e1003723
24068945
Nat Genet. 2011 Oct 09;43(11):1066-73
21983784
PLoS One. 2011;6(11):e27828
22114704
PLoS Pathog. 2009 Aug;5(8):e1000559
19696895
Annu Rev Cell Dev Biol. 2012;28:137-61
22974247
Gut. 2016 May;65(5):788-96
25731871
J Immunol. 2014 Feb 15;192(4):1835-46
24453255
J Clin Invest. 2008 Feb;118(2):545-59
18188453
Cytokine. 2000 Nov;12(11):1581-96
11052809
J Exp Med. 1992 Dec 1;176(6):1693-702
1460426
Nat Med. 2015 Mar;21(3):248-55
25686105
Nat Rev Immunol. 2013 Sep;13(9):679-92
23954936
Nat Immunol. 2010 Jan;11(1):63-9
19915568
J Immunol. 2008 Jul 15;181(2):918-30
18606643
J Cell Biol. 2009 Oct 5;187(1):61-70
19805629
Immunity. 2006 Sep;25(3):473-85
16949315
J Biol Chem. 2002 Jun 14;277(24):21119-22
11967258
Nat Immunol. 2009 Nov;10(11):1208-14
19767757
Nature. 2006 Aug 10;442(7103):651-6
16862125
PLoS Pathog. 2014 Dec 04;10(12):e1004525
25474208
Nat Immunol. 2012 Jan 22;13(3):246-54
22267217
Nat Immunol. 2007 Feb;8(2):198-205
17187069
J Immunol. 2009 Jan 15;182(2):1146-54
19124758
J Immunol. 2013 Nov 15;191(10):5239-46
24123685
Nat Immunol. 2014 Jun;15(6):538-45
24777530
J Immunol. 1999 May 1;162(9):5367-73
10228013
Nature. 2015 Oct 29;526(7575):666-71
26375259
Cell Host Microbe. 2012 Mar 15;11(3):277-89
22423967
Cell. 2014 May 22;157(5):1013-22
24855941
Nat Immunol. 2013 Dec;14(12):1247-55
24185614
Nature. 2015 Oct 29;526(7575):660-5
26375003
J Biol Chem. 2000 Dec 29;275(52):41082-6
11053425
Cell. 1996 Jun 14;85(6):817-27
8681377
Am J Hum Genet. 2008 May;82(5):1202-10
18439550
Immunology. 2008 Aug;124(4):469-79
18217948
J Exp Med. 2010 Apr 12;207(4):777-92
20351059
FEBS Lett. 2014 Aug 25;588(17):2830-6
24960071
Nucleic Acids Res. 2009 Jan;37(Database issue):D412-6
18940858