Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines.
Inflammatory agonists such as lipopolysaccharide (LPS) induce robust systemic as well as CNS responses after peripheral administration. Responses in the innate immune system require triggering of toll-like receptor 4 (TLR4), but the origin of CNS sequelas has been controversial. We demonstrate expression of TLR4 transcripts in mouse brain in the meninges, ventricular ependyma, circumventricular organs, along the vasculature, and in parenchymal microglia. The contribution of TLR4 expressed in CNS resident versus hematopoietic cells to the development of CNS inflammation was examined using chimeric mice. Reciprocal bone marrow chimeras between wild-type and TLR4 mutant mice show that TLR4 on CNS resident cells is critically required for sustained inflammation in the brain after systemic LPS administration. Hematopoietic TLR4 alone supported the systemic release of acute phase cytokines, but transcription of proinflammatory genes in the CNS was reduced in duration. In contrast, TLR4 function in radiation-resistant cells was sufficient for inflammatory progression in the brains of chimeric mice, despite the striking absence of cytokine elevations in serum. Surprisingly, a temporal rise in serum corticosterone was also dependent on TLR4 signaling in nonhematopoietic cells. Our findings demonstrate a requirement for TLR4 function in CNS-resident cells, independent of systemic cytokine effects, for sustained CNS-specific inflammation and corticosterone rise during endotoxemia.
Chakravarty
Sumana
S
Section on Functional Neuroanatomy, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.
Herkenham
Miles
M
D000818:Animals; D016026:Bone Marrow Transplantation; D001921:Brain / Q000378:metabolism*; D000073883:CX3C Chemokine Receptor 1; D019070:Cell Lineage; D002831:Choroid Plexus / Q000378:metabolism; D003345:Corticosterone / Q000097:blood; D016207:Cytokines / Q000502:physiology; D004660:Encephalitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D019446:Endotoxemia / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D020672:I-kappa B Proteins / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D008578:Meninges / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011828:Radiation Chimera; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000378:metabolism; D051197:Toll-Like Receptor 4
D000073883:CX3C Chemokine Receptor 1; C471885:Cx3cr1 protein, mouse; D016207:Cytokines; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C000606205:Nfkbia protein, mouse; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C482199:lipopolysaccharide, E coli O55-B5; D000072000:NF-KappaB Inhibitor alpha; D003345:Corticosterone
Neuroscience. 1999 Mar;90(3):923-31
10218792
J Neuroimmunol. 1999 Jan 1;93(1-2):72-80
10378870
J Neurochem. 1999 Jul;73(1):309-21
10386984
J Biol Chem. 2000 Mar 31;275(13):9773-81
10734131
J Neurochem. 2000 Nov;75(5):2061-70
11032895
Infect Immun. 2000 Dec;68(12):7010-7
11083826
FASEB J. 2001 Jan;15(1):155-163
11149903
J Immunol. 2001 Feb 1;166(3):2018-24
11160251
Invest Ophthalmol Vis Sci. 2001 Nov;42(12):2867-77
11687531
J Neurosci. 2002 Apr 1;22(7):2478-86
11923412
Am J Physiol Regul Integr Comp Physiol. 2002 Nov;283(5):R1104-17
12376404
J Neuropathol Exp Neurol. 2002 Nov;61(11):1013-21
12430718
Brain Behav Immun. 2003 Feb;17(1):13-9
12615045
Eur J Immunol. 2003 Apr;33(4):1127-38
12672079
Biochem Biophys Res Commun. 2003 Jun 6;305(3):649-55
12763043
J Neurosci. 2003 Jun 15;23(12):5004-11
12832523
J Neurosci. 2003 Jun 15;23(12):5197-207
12832544
J Neurosci. 2003 Jul 2;23(13):5607-16
12843263
Infect Immun. 2003 Dec;71(12):6799-807
14638766
Cell Mol Neurobiol. 1990 Mar;10(1):145-57
2334945
Science. 1987 Oct 23;238(4826):524-6
2443979
Nature. 1983 Aug 4-10;304(5925):449-51
6603577
J Immunol. 1994 Sep 15;153(6):2653-63
7521367
J Pharmacol Exp Ther. 1995 May;273(2):909-17
7752096
Proc Natl Acad Sci U S A. 1994 Nov 22;91(24):11393-7
7972071
Brain Res. 1996 Mar 25;713(1-2):64-9
8724976
J Comp Neurol. 1996 Jul 15;371(1):85-103
8835720
Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10985-90
9380746
Science. 1998 Dec 11;282(5396):2085-8
9851930
Physiol Rev. 1999 Jan;79(1):1-71
9922367