Below the surface: The inner lives of TLR4 and TLR9

Abstract

TLRs are a class of pattern recognition receptors (PRRs) that detect invading microbes by recognizing pathogen-associated molecular patterns (PAMPs). Upon PAMP engagement, TLRs activate a signaling cascade that leads to the production of inflammatory mediators. The localization of TLRs, either on the plasma membrane or in the endolysosomal compartment, has been considered to be a fundamental aspect to determine to which ligands the receptors bind, and which transduction pathways are induced. However, new observations have challenged this view by identifying complex trafficking events that occur upon TLR-ligand binding. These findings have highlighted the central role that endocytosis and receptor trafficking play in the regulation of the innate immune response. Here, we review the TLR4 and TLR9 transduction pathways and the importance of their different subcellular localization during the inflammatory response. Finally, we discuss the implications of TLR9 subcellular localization in autoimmunity.

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     Ewald SE, Lee BL, Lau L, et al. The ectodomain of Toll‐like receptor 9 is cleaved to generate a functional receptor. Nature. 2008;456:658‐662.

     Not in our library10.1038/nature07405

110. 110.

     Park B, Brinkmann MM, Spooner E, Lee CC, Kim YM, Ploegh HL. Proteolytic cleavage in an endolysosomal compartment is required for activation of Toll‐like receptor 9. Nat Immunol. 2008;9:1407‐1414.

     Not in our library10.1038/ni.1669

111. 111.

     Seya T, Shingai M, Matsumoto M. [Toll‐like receptors that sense viral infection]. Uirusu. 2004;54:1‐8.

     Not in our library10.2222/jsv.54.1

112. 112.

     Sepulveda FE, Maschalidi S, Colisson R, et al. Critical role for asparagine endopeptidase in endocytic Toll‐like receptor signaling in dendritic cells. Immunity. 2009;31:737‐748.

     Not in our library10.1016/j.immuni.2009.09.013

113. 113.

     Ewald SE, Engel A, Lee J, Wang M, Bogyo M, Barton GM. Nucleic acid recognition by Toll‐like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase. J Exp Med. 2011;208:643‐651.

     Not in our library10.1084/jem.20100682

114. 114.

     Chockalingam A, Cameron JL, Brooks JC, Leifer CA. Negative regulation of signaling by a soluble form of toll‐like receptor 9. Eur J Immunol. 2011;41:2176‐2184.

     Not in our library10.1002/eji.201041034

115. 115.

     Lee S, Kang D, Ra EA, Lee TA, Ploegh HL, Park B. Negative self‐regulation of TLR9 signaling by its N‐terminal proteolytic cleavage product. J Immunol. 2014;193:3726‐3735.

     Not in our library10.4049/jimmunol.1400210

116. 116.

     Onji M, Kanno A, Saitoh S, et al. An essential role for the N‐terminal fragment of Toll‐like receptor 9 in DNA sensing. Nat Commun. 2013;4:1949.

     Not in our library10.1038/ncomms2949

117. 117.

     Sinha SS, Cameron J, Brooks JC, Leifer CA. Complex negative regulation of TLR9 by multiple proteolytic cleavage events. J Immunol. 2016;197:1343‐1352.

     Not in our library10.4049/jimmunol.1502357

118. 118.

     Aksoy E, Taboubi S, Torres D, et al. The p110delta isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nat Immunol. 2012;13:1045‐1054.

     Not in our library10.1038/ni.2426

119. 119.

     Bonham KS, Orzalli MH, Hayashi K, et al. A promiscuous lipid‐binding protein diversifies the subcellular sites of toll‐like receptor signal transduction. Cell. 2014;156:705‐716.

     Not in our library10.1016/j.cell.2014.01.019

120. 120.

     Sato A, Linehan MM, Iwasaki A. Dual recognition of herpes simplex viruses by TLR2 and TLR9 in dendritic cells. Proc Natl Acad Sci U S A. 2006;103:17343‐17348.

     Not in our library10.1073/pnas.0605102103

121. 121.
     A Decoy Peptide that Disrupts TIRAP Recruitment to TLRs Is Protective in a Murine Model of Influenza · 2015

     Not checked
122. 122.

     Kavran JM, Klein DE, Lee A, et al. Specificity and promiscuity in phosphoinositide binding by pleckstrin homology domains. J Biol Chem. 1998;273:30497‐30508.

     Not in our library10.1074/jbc.273.46.30497

123. 123.

     Ve T, Vajjhala PR, Hedger A, et al. Structural basis of TIR‐domain‐assembly formation in MAL‐ and MyD88‐dependent TLR4 signaling. Nat Struct Mol Biol. 2017;24:743‐751.

     Not in our library10.1038/nsmb.3444

124. 124.

     Javmen A, Szmacinski H, Lakowicz JR, Toshchakov VY. Blocking TIR domain interactions in TLR9 signaling. J Immunol. 2018;201:995‐1006.

     Not in our library10.4049/jimmunol.1800194

125. 125.

     Latz E, Verma A, Visintin A, et al. Ligand‐induced conformational changes allosterically activate Toll‐like receptor 9. Nat Immunol. 2007;8:772‐779.

     Not in our library10.1038/ni1479

126. 126.

     Suzuki N, Suzuki S, Duncan GS, et al. Severe impairment of interleukin‐1 and Toll‐like receptor signalling in mice lacking IRAK‐4. Nature. 2002;416:750‐756.

     Not in our library10.1038/nature736

127. 127.

     Kawagoe T, Sato S, Matsushita K, et al. Sequential control of Toll‐like receptor‐dependent responses by IRAK1 and IRAK2. Nat Immunol. 2008;9:684‐691.

     Not in our library10.1038/ni.1606

128. 128.

     Hacker H, Vabulas RM, Takeuchi O, Hoshino K, Akira S, Wagner H. Immune cell activation by bacterial CpG‐DNA through myeloid differentiation marker 88 and tumor necrosis factor receptor‐associated factor (TRAF)6. J Exp Med. 2000;192:595‐600.

     Not in our library10.1084/jem.192.4.595

129. 129.

     Siggs OM, Berger M, Krebs P, et al. A mutation of Ikbkg causes immune deficiency without impairing degradation of IkappaB alpha. Proc Natl Acad Sci U S A. 2010;107:3046‐3051.

     Not in our library10.1073/pnas.0915098107

130. 130.

     Min Y, Kim MJ, Lee S, Chun E, Lee KY. Inhibition of TRAF6 ubiquitin‐ligase activity by PRDX1 leads to inhibition of NFKB activation and autophagy activation. Autophagy. 2018;14:1347‐1358.

     Not in our library10.1080/15548627.2018.1474995

131. 131.

     Scheidereit C. IkappaB kinase complexes: gateways to NF‐kappaB activation and transcription. Oncogene. 2006;25:6685‐6705.

     Not in our library10.1038/sj.onc.1209934

132. 132.

     Takaesu G, Surabhi RM, Park KJ, Ninomiya‐Tsuji J, Matsumoto K, Gaynor RB. TAK1 is critical for IkappaB kinase‐mediated activation of the NF‐kappaB pathway. J Mol Biol. 2003;326:105‐115.

     Not in our library10.1016/s0022-2836(02)01404-3

133. 133.

     Bonizzi G, Bebien M, Otero DC, et al. Activation of IKKalpha target genes depends on recognition of specific kappaB binding sites by RelB:p52 dimers. Embo j. 2004;23:4202‐4210.

     Not in our library10.1038/sj.emboj.7600391

134. 134.

     Deng L, Wang C, Spencer E, et al. Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin‐conjugating enzyme complex and a unique polyubiquitin chain. Cell. 2000;103:351‐361.

     Not in our library10.1016/s0092-8674(00)00126-4

135. 135.

     Wang C, Deng L, Hong M, Akkaraju GR, Inoue J, Chen ZJ. TAK1 is a ubiquitin‐dependent kinase of MKK and IKK. Nature. 2001;412:346‐351.

     Not in our library10.1038/35085597

136. 136.

     Ninomiya‐Tsuji J, Kishimoto K, Hiyama A, Inoue J, Cao Z, Matsumoto K. The kinase TAK1 can activate the NIK‐I kappaB as well as the MAP kinase cascade in the IL‐1 signalling pathway. Nature. 1999;398:252‐256.

     Not in our library10.1038/18465

137. 137.

     Negishi H, Fujita Y, Yanai H, et al. Evidence for licensing of IFN‐gamma‐induced IFN regulatory factor 1 transcription factor by MyD88 in Toll‐like receptor‐dependent gene induction program. Proc Natl Acad Sci U S A. 2006;103:15136‐15141.

     Not in our library10.1073/pnas.0607181103

138. 138.

     Takaoka A, Yanai H, Kondo S, et al. Integral role of IRF‐5 in the gene induction programme activated by Toll‐like receptors. Nature. 2005;434:243‐249.

     Not in our library10.1038/nature03308

139. 139.

     Hoshino K, Sasaki I, Sugiyama T, et al. Critical role of IkappaB kinase alpha in TLR7/9‐induced type I IFN production by conventional dendritic cells. J Immunol. 2010;184:3341‐3345.

     Not in our library10.4049/jimmunol.0901648

140. 140.

     Schmitz F, Heit A, Guggemoos S, et al. Interferon‐regulatory‐factor 1 controls Toll‐like receptor 9‐mediated IFN‐beta production in myeloid dendritic cells. Eur J Immunol. 2007;37:315‐327.

     Not in our library10.1002/eji.200636767

141. 141.

     Yang K, Puel A, Zhang S, et al. Human TLR‐7‐, ‐8‐, and ‐9‐mediated induction of IFN‐alpha/beta and ‐lambda Is IRAK‐4 dependent and redundant for protective immunity to viruses. Immunity. 2005;23:465‐478.

     Not in our library10.1016/j.immuni.2005.09.016

142. 142.

     Honda K, Yanai H, Mizutani T, et al. Role of a transductional‐transcriptional processor complex involving MyD88 and IRF‐7 in Toll‐like receptor signaling. Proc Natl Acad Sci U S A. 2004;101:15416‐15421.

     Not in our library10.1073/pnas.0406933101

143. 143.

     Hacker H, Redecke V, Blagoev B, et al. Specificity in Toll‐like receptor signalling through distinct effector functions of TRAF3 and TRAF6. Nature. 2006;439:204‐207.

     Not in our library10.1038/nature04369

144. 144.

     Oganesyan G, Saha SK, Guo B, et al. Critical role of TRAF3 in the Toll‐like receptor‐dependent and ‐independent antiviral response. Nature. 2006;439:208‐211.

     Not in our library10.1038/nature04374

145. 145.

     Uematsu S, Sato S, Yamamoto M, et al. Interleukin‐1 receptor‐associated kinase‐1 plays an essential role for Toll‐like receptor (TLR)7‐ and TLR9‐mediated interferon‐{alpha} induction. J Exp Med. 2005;201:915‐923.

     Not in our library10.1084/jem.20042372

146. 146.

     Kawai T, Sato S, Ishii KJ, et al. Interferon‐alpha induction through Toll‐like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6. Nat Immunol. 2004;5:1061‐1068.

     Not in our library10.1038/ni1118

147. 147.

     Hoshino K, Sugiyama T, Matsumoto M, et al. IkappaB kinase‐alpha is critical for interferon‐alpha production induced by Toll‐like receptors 7 and 9. Nature. 2006;440:949‐953.

     Not in our library10.1038/nature04641

148. 148.

     Shinohara ML, Lu L, Bu J, et al. Osteopontin expression is essential for interferon‐alpha production by plasmacytoid dendritic cells. Nat Immunol. 2006;7:498‐506.

     Not in our library10.1038/ni1327

149. 149.

     Cao W, Manicassamy S, Tang H, et al. Toll‐like receptor‐mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin‐sensitive PI(3)K‐mTOR‐p70S6K pathway. Nat Immunol. 2008;9:1157‐1164.

     Not in our library10.1038/ni.1645

150. 150.

     Lou H, Pickering MC. Extracellular DNA and autoimmune diseases. Cell Mol Immunol. 2018;15:746‐755.

     Not in our library10.1038/cmi.2017.136

151. 151.

     Dieker J, Hilbrands L, Thielen A, Dijkman H, Berden JH, van der Vlag J. Enhanced activation of dendritic cells by autologous apoptotic microvesicles in MRL/lpr mice. Arthritis Res Ther. 2015;17:103.

     Not in our library10.1186/s13075-015-0617-2

152. 152.

     Yasuda K, Richez C, Uccellini MB, et al. Requirement for DNA CpG content in TLR9‐dependent dendritic cell activation induced by DNA‐containing immune complexes. J Immunol. 2009;183:3109‐3117.

     Not in our library10.4049/jimmunol.0900399

153. 153.

     Asagiri M, Hirai T, Kunigami T, et al. Cathepsin K‐dependent toll‐like receptor 9 signaling revealed in experimental arthritis. Science. 2008;319:624‐627.

     Not in our library10.1126/science.1150110

154. 154.

     Papadimitraki ED, Choulaki C, Koutala E, et al. Expansion of toll‐like receptor 9‐expressing B cells in active systemic lupus erythematosus: implications for the induction and maintenance of the autoimmune process. Arthritis Rheum. 2006;54:3601‐3611.

     Not in our library10.1002/art.22197

155. 155.

     Jin O, Kavikondala S, Sun L, et al. Systemic lupus erythematosus patients have increased number of circulating plasmacytoid dendritic cells, but decreased myeloid dendritic cells with deficient CD83 expression. Lupus. 2008;17:654‐662.

     Not in our library10.1177/0961203308089410

156. 156.

     Mortezagholi S, Babaloo Z, Rahimzadeh P, et al. Evaluation of TLR9 expression on PBMCs and CpG ODN‐TLR9 ligation on IFN‐alpha production in SLE patients. Immunopharmacol Immunotoxicol. 2017;39:11‐18.

     Not in our library10.1080/08923973.2016.1263859

157. 157.

     Christensen SR, Kashgarian M, Alexopoulou L, Flavell RA, Akira S, Shlomchik MJ. Toll‐like receptor 9 controls anti‐DNA autoantibody production in murine lupus. J Exp Med. 2005;202:321‐331.

     Not in our library10.1084/jem.20050338

158. 158.

     Nickerson KM, Christensen SR, Shupe J, et al. TLR9 regulates TLR7‐ and MyD88‐dependent autoantibody production and disease in a murine model of lupus. J Immunol. 2010;184:1840‐1848.

     Not in our library10.4049/jimmunol.0902592

159. 159.

     Santiago‐Raber ML, Dunand‐Sauthier I, Wu T, et al. Critical role of TLR7 in the acceleration of systemic lupus erythematosus in TLR9‐deficient mice. J Autoimmun. 2010;34:339‐348.

     Not in our library10.1016/j.jaut.2009.11.001

160. 160.

     Fukui R, Saitoh S, Kanno A, et al. Unc93B1 restricts systemic lethal inflammation by orchestrating Toll‐like receptor 7 and 9 trafficking. Immunity. 2011;35:69‐81.

     Not in our library10.1016/j.immuni.2011.05.010

161. 161.

     Hoffmann MH, Skriner K, Herman S, et al. Nucleic acid‐stimulated antigen‐presenting cells trigger T cells to induce disease in a rat transfer model of inflammatory arthritis. J Autoimmun. 2011;36:288‐300.

     Not in our library10.1016/j.jaut.2011.02.007

162. 162.

     Miles K, Heaney J, Sibinska Z, et al. A tolerogenic role for Toll‐like receptor 9 is revealed by B‐cell interaction with DNA complexes expressed on apoptotic cells. Proc Natl Acad Sci U S A. 2012;109:887‐892.

     Not in our library10.1073/pnas.1109173109

163. 163.

     Paulsen F, Pufe T, Conradi L, et al. Antimicrobial peptides are expressed and produced in healthy and inflamed human synovial membranes. J Pathol. 2002;198:369‐377.

     Not in our library10.1002/path.1224

164. 164.

     Lai Y, Gallo RL. AMPed up immunity: how antimicrobial peptides have multiple roles in immune defense. Trends Immunol. 2009;30:131‐141.

     Not in our library10.1016/j.it.2008.12.003

165. 165.

     Lande R, Gregorio J, Facchinetti V, et al. Plasmacytoid dendritic cells sense self‐DNA coupled with antimicrobial peptide. Nature. 2007;449:564‐569.

     Not in our library10.1038/nature06116

166. 166.

     Nestle FO, Conrad C, Tun‐Kyi A, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon‐alpha production. J Exp Med. 2005;202:135‐143.

     Not in our library10.1084/jem.20050500

167. 167.

     Lebre MC, van der Aar AM, van Baarsen L, et al. Human keratinocytes express functional Toll‐like receptor 3, 4, 5, and 9. J Invest Dermatol. 2007;127:331‐341.

     Not in our library10.1038/sj.jid.5700530

168. 168.

     Morizane S, Yamasaki K, Mühleisen B, et al. Cathelicidin antimicrobial peptide LL‐37 in psoriasis enables keratinocyte reactivity against TLR9 ligands. J Invest Dermatol. 2012;132:135‐143.

     Not in our library10.1038/jid.2011.259

169. 169.

     McAlpine W, Sun L, Wang KW, et al. Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8‐WDR41‐C9ORF72 complex function. Proc Natl Acad Sci U S A. 2018;115(49):E11523‐E11531.

     Not in our library10.1073/pnas.1814753115

170. 170.

     Zhang Y, Burberry A, Wang JY, et al. The C9orf72‐interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis. Genes Dev. 2018;32:929‐943.

     Not in our library10.1101/gad.313932.118

171. 171.

     Farg MA, Sundaramoorthy V, Sultana JM, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014;23:3579‐3595.

     Not in our library10.1093/hmg/ddu068

172. 172.

     Rosadini CV, Kagan JC. Early innate immune responses to bacterial LPS. Curr Opin Immunol. 2017;44:14‐19.

     Not in our library10.1016/j.coi.2016.10.005

Cited by papers we hold 2

• TLR Agonists as Mediators of Trained Immunity: Mechanistic Insight and Immunotherapeutic Potential to Combat Infection · 2021
  No notice
• TLR4 and CD14 trafficking and its influence on LPS-induced pro-inflammatory signaling · 2020
  No notice

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