title: Radiation takes its Toll.
abstract: The ability to recognize and respond to universal molecular patterns on invading microorganisms allows our immune system to stay on high alert, sensing danger to our self-integrity. Our own damaged cells and tissues in pathological situations activate similar warning systems as microbes. In this way, the body is able to mount a response that is appropriate to the danger. Toll-like receptors are at the heart of this pattern recognition system that initiates innate pro-oxidant, pro-inflammatory signaling cascades and ultimately bridges recognition of danger to adaptive immunity. The acute inflammatory lesions that are formed segue into resolution of inflammation, repair and healing or, more dysfunctionally, into chronic inflammation, autoimmunity, excessive tissue damage and carcinogenesis. Redox is at the nexus of this decision making process and is the point at which ionizing radiation initially intercepts to trigger similar responses to self-damage. In this review we discuss our current understanding of how radiation-damaged cells interact with Toll-like receptors and how the immune systems interprets these radiation-induced danger signals in the context of whole-body exposures and during local tumor irradiation.
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA.
authors.forename: Josephine A
authors.initials: JA
authors.lastname: Ratikan
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA.
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Micewicz
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Xie
authors.affiliation: Department of Radiation Oncology, David Geffen School of Medicine, University of California at Los Angeles, CA, USA. Electronic address: dschaue@mednet.ucla.edu.
authors.forename: Dörthe
authors.initials: D
authors.lastname: Schaue
mesh_terms: D006801:Humans; D007107:Immune System / Q000276:immunology / Q000528:radiation effects; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D011832:Radiation Injuries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors
keywords: Inflammation; Radiation; Reactive oxygen species; Redox; Toll-like receptors
references.citation: Radiat Res. 1998 May;149(5):472-81
references.pmid: 9588358
references.citation: PLoS One. 2011;6(8):e23682
references.pmid: 21887294
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2452-7
references.pmid: 14983030
references.citation: Radiat Environ Biophys. 2000 Jun;39(2):79-87
references.pmid: 10929376
references.citation: Mutat Res Genet Toxicol Environ Mutagen. 2014 Nov 1;774:22-8
references.pmid: 25440907
references.citation: Am J Physiol. 1957 Oct;191(1):124-30
references.pmid: 13478698
references.citation: Biochim Biophys Acta. 2010 Jan;1800(1):40-6
references.pmid: 19854240
references.citation: J Clin Invest. 2012 Mar;122(3):787-95
references.pmid: 22378047
references.citation: Semin Radiat Oncol. 2015 Jan;25(1):4-10
references.pmid: 25481260
references.citation: Oncogenesis. 2013 Aug 12;2:e62
references.pmid: 23939014
references.citation: Cell. 2014 Jul 31;158(3):506-21
references.pmid: 25083866
references.citation: Immunity. 2009 Jun 19;30(6):766-75
references.pmid: 19538928
references.citation: Nat Med. 1999 Nov;5(11):1249-55
references.pmid: 10545990
references.citation: Curr Med Chem. 2012;19(12):1765-70
references.pmid: 22414085
references.citation: Med Hypotheses. 1986 Nov;21(3):267-71
references.pmid: 3642198
references.citation: Radiother Oncol. 2004 Sep;72(3):297-303
references.pmid: 15450728
references.citation: Int J Radiat Oncol Biol Phys. 2005 Jul 1;62(3):862-71
references.pmid: 15936571
references.citation: Nat Med. 2007 Sep;13(9):1050-9
references.pmid: 17704786
references.citation: Nat Commun. 2014;5:3492
references.pmid: 24637670
references.citation: Immunopharmacol Immunotoxicol. 1988;10(1):109-16
references.pmid: 2834428
references.citation: Int J Mol Med. 2013 Dec;32(6):1407-14
references.pmid: 24085242
references.citation: Immunity. 2011 May 27;34(5):637-50
references.pmid: 21616434
references.citation: Mediators Inflamm. 2010;2010. pii: 672395. doi: 10.1155/2010/672395
references.pmid: 20706656
references.citation: Immunol Cell Biol. 2013 Nov-Dec;91(10):597-8
references.pmid: 24060964
references.citation: Int J Radiat Biol. 1997 Jul;72(1):45-53
references.pmid: 9246193
references.citation: Clin Cancer Res. 2009 Dec 1;15(23):7238-45
references.pmid: 19920105
references.citation: Curr Opin Gastroenterol. 2012 Mar;28(2):124-9
references.pmid: 22241076
references.citation: J Exp Med. 2006 May 15;203(5):1259-71
references.pmid: 16636135
references.citation: Mol Cell Biol. 2008 Nov;28(21):6557-67
references.pmid: 18779317
references.citation: PLoS Genet. 2011 Mar;7(3):e1001360
references.pmid: 21483755
references.citation: Nature. 2013 Sep 19;501(7467):416-20
references.pmid: 23975097
references.citation: Br J Dermatol. 2007 Dec;157 Suppl 2:8-13
references.pmid: 18067624
references.citation: Proc Natl Acad Sci U S A. 2013 May 14;110(20):E1857-66
references.pmid: 23630282
references.citation: PLoS One. 2012;7(1):e29357
references.pmid: 22238604
references.citation: Oncogene. 2013 Dec 12;32(50):5574-81
references.pmid: 23995793
references.citation: Curr Med Chem. 2012;19(12):1741-50
references.pmid: 22414082
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Jan;286(1):G166-73
references.pmid: 14525729
references.citation: Radiat Res. 1964 Nov;23:333-49
references.pmid: 14229117
references.citation: Radiat Res. 2010 Apr;173(4):406-17
references.pmid: 20334512
references.citation: J Exp Med. 2011 Sep 26;208(10):1989-2003
references.pmid: 21930769
references.citation: J Immunol. 2008 Jun 15;180(12):8280-5
references.pmid: 18523294
references.citation: Int J Radiat Biol. 2011 Aug;87(8):839-45
references.pmid: 21401317
references.citation: Science. 2002 Apr 12;296(5566):301-5
references.pmid: 11951032
references.citation: Int J Radiat Oncol Biol Phys. 1995 Oct 15;33(3):619-26
references.pmid: 7558951
references.citation: Oncogene. 2001 Oct 25;20(48):7085-95
references.pmid: 11704832
references.citation: Int J Radiat Biol. 2009 Dec;85(12):1126-36
references.pmid: 19995238
references.citation: Cancer Res. 2010 Nov 1;70(21):8886-95
references.pmid: 20940400
references.citation: Radiother Oncol. 2011 Jun;99(3):313-6
references.pmid: 21704400
references.citation: PLoS One. 2011;6(7):e22504
references.pmid: 21799877
references.citation: Clin Vaccine Immunol. 2008 Jan;15(1):138-46
references.pmid: 17978010
references.citation: J Clin Invest. 2012 Nov;122(11):4118-29
references.pmid: 23023703
references.citation: J Radiat Res. 2011;52(6):828-33
references.pmid: 22104272
references.citation: PLoS Med. 2009 Jan 13;6(1):e10
references.pmid: 19143470
references.citation: Biol Lett. 2012 Aug 23;8(4):594-7
references.pmid: 22496076
references.citation: Infect Immun. 2000 Dec;68(12):7010-7
references.pmid: 11083826
references.citation: J Clin Oncol. 2010 Oct 1;28(28):4324-32
references.pmid: 20697067
references.citation: Trends Immunol. 2013 Aug;34(8):379-89
references.pmid: 23660392
references.citation: Nature. 1997 Jul 24;388(6640):394-7
references.pmid: 9237759
references.citation: Exp Eye Res. 2007 Oct;85(4):462-72
references.pmid: 17765224
references.citation: Mol Cell Biol. 1994 Feb;14(2):1322-32
references.pmid: 8289810
references.citation: Circ Res. 2011 Jan 21;108(2):235-48
references.pmid: 21252151
references.citation: J Dermatol Sci. 2008 Jul;51(1):11-8
references.pmid: 18325741
references.citation: FEBS J. 2010 May;277(9):2051-66
references.pmid: 20345905
references.citation: Annu Rev Immunol. 2003;21:685-711
references.pmid: 12615891
references.citation: Radiat Environ Biophys. 2007 Mar;46(1):21-9
references.pmid: 17072632
references.citation: Cancer Res. 2013 Dec 15;73(24):7211-21
references.pmid: 24154870
references.citation: J Radiat Res. 2004 Sep;45(3):423-33
references.pmid: 15613788
references.citation: J Immunol. 2002 May 15;168(10):5252-9
references.pmid: 11994482
references.citation: Radiat Res. 2004 Jul;162(1):1-19
references.pmid: 15222781
references.citation: Oncogene. 2008 Jan 7;27(2):218-24
references.pmid: 18176603
references.citation: Nat Med. 2007 May;13(5):552-9
references.pmid: 17479101
references.citation: PLoS One. 2012;7(3):e32542
references.pmid: 22396773
references.citation: Radiat Res. 2012 May;177(5):584-93
references.pmid: 22463680
references.citation: Immunity. 2008 Jul 18;29(1):21-32
references.pmid: 18631454
references.citation: Radiat Res. 1998 Jun;149(6):570-8
references.pmid: 9611095
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13254-9
references.pmid: 16129828
references.citation: DNA Repair (Amst). 2012 Aug 1;11(8):657-65
references.pmid: 22682873
references.citation: J Radiat Res. 2014 Jul;55(4):674-82
references.pmid: 24570173
references.citation: Adv Exp Med Biol. 2013;765:371-7
references.pmid: 22879058
references.citation: J Immunol. 2009 Jul 15;183(2):787-91
references.pmid: 19570822
references.citation: Cell Death Dis. 2013;4:e649
references.pmid: 23722538
references.citation: Cancer Microenviron. 2009 Sep;2 Suppl 1:205-14
references.pmid: 19685283
references.citation: Cancer Lett. 2015 Jan 1;356(1):17-21
references.pmid: 24041870
references.citation: Nature. 2002 Apr 11;416(6881):603-7
references.pmid: 11948342
references.citation: Int J Cancer. 2006 Feb 1;118(3):633-42
references.pmid: 16106417
references.citation: Mediators Inflamm. 2010;2010. pii: 916425. doi: 10.1155/2010/916425
references.pmid: 20706658
references.citation: Clin Cancer Res. 2009 Sep 1;15(17):5379-88
references.pmid: 19706802
references.citation: Int J Radiat Oncol Biol Phys. 2012 Jul 15;83(4):1306-10
references.pmid: 22208977
references.citation: Nature. 2012 Sep 13;489(7415):220-30
references.pmid: 22972295
references.citation: J Clin Invest. 2010 Apr;120(4):1285-97
references.pmid: 20237413
references.citation: Semin Radiat Oncol. 2015 Jan;25(1):34-9
references.pmid: 25481264
references.citation: Acta Derm Venereol. 2001 Oct-Nov;81(5):329-33
references.pmid: 11800138
references.citation: Nature. 2003 Oct 2;425(6957):516-21
references.pmid: 14520412
references.citation: Radiat Res. 2012 Dec;178(6):505-23
references.pmid: 23106210
references.citation: Nature. 2008 Mar 6;452(7183):103-7
references.pmid: 18288107
references.citation: Oncoimmunology. 2014 Apr 25;3:e28518
references.pmid: 25071979
references.citation: Radiat Res. 1995 Aug;143(2):187-93
references.pmid: 7543208
references.citation: Clin Dev Immunol. 2011;2011:439752
references.pmid: 22162711
references.citation: Immunity. 2014 Nov 20;41(5):830-42
references.pmid: 25517615
references.citation: Nat Rev Immunol. 2013 Jun;13(6):453-60
references.pmid: 23681101
references.citation: Dis Colon Rectum. 2000 Nov;43(11):1582-1587; discussion 1587-8
references.pmid: 11089597
references.citation: Oncogene. 2006 Oct 30;25(51):6731-48
references.pmid: 17072325
references.citation: Nat Rev Cancer. 2009 Jan;9(1):57-63
references.pmid: 19052556
references.citation: Nature. 1998 Mar 19;392(6673):245-52
references.pmid: 9521319
references.citation: Lab Invest. 2014 Nov;94(11):1188-99
references.pmid: 25068657
references.citation: Nature. 2012 May 10;485(7397):251-5
references.pmid: 22535248
references.citation: Antioxid Redox Signal. 2011 Apr 1;14(7):1315-35
references.pmid: 20969478
references.citation: Nature. 2005 Aug 25;436(7054):1186-90
references.pmid: 15995699
references.citation: Int J Radiat Biol. 1999 Jun;75(6):757-66
references.pmid: 10405006
references.citation: Int J Radiat Oncol Biol Phys. 2010 Jul 15;77(4):1198-205
references.pmid: 20610040
references.citation: Cell Death Dis. 2013;4:e962
references.pmid: 24336082
references.citation: J Exp Med. 2011 Sep 26;208(10):2005-16
references.pmid: 21930765
references.citation: J Immunol. 2015 Feb 1;194(3):1178-89
references.pmid: 25539818
references.citation: J Immunol. 2007 May 15;178(10):6573-80
references.pmid: 17475888
references.citation: Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1:1-13
references.pmid: 2700931
references.citation: Int J Cancer. 2004 May 1;109(5):685-90
references.pmid: 14999775
references.citation: Immunol Rev. 2007 Dec;220:60-81
references.pmid: 17979840
references.citation: Science. 2008 Apr 11;320(5873):226-30
references.pmid: 18403709
references.citation: Nature. 2010 Mar 4;464(7285):104-7
references.pmid: 20203610
references.citation: J Immunol. 2014 Dec 15;193(12):6124-34
references.pmid: 25385820
references.citation: Radiat Res. 2010 Mar;173(3):298-309
references.pmid: 20199215
references.citation: Radiat Oncol. 2014;9(1):89
references.pmid: 24678590
references.citation: Gut. 2012 Jun;61(6):829-38
references.pmid: 22027478
references.citation: Biull Eksp Biol Med. 1962 Nov;54:39-42
references.pmid: 13949173
references.citation: Cell Death Differ. 2014 Jan;21(1):39-49
references.pmid: 23832118
references.citation: Immunity. 2014 Nov 20;41(5):843-52
references.pmid: 25517616
references.citation: PLoS One. 2012;7(3):e33044
references.pmid: 22479357
references.citation: Cell Death Differ. 2007 Oct;14(10):1848-50
references.pmid: 17657249
references.citation: J Am Coll Cardiol. 1999 Aug;34(2):561-6
references.pmid: 10440173
references.citation: J Pharmacol Exp Ther. 2013 Jul;346(1):75-85
references.pmid: 23596059
references.citation: Cancer Res. 2004 Aug 1;64(15):5074-7
references.pmid: 15289307
references.citation: Arch Virol. 1978;56(4):309-15
references.pmid: 348157
references.citation: J Clin Invest. 2007 Aug;117(8):2197-204
references.pmid: 17657310