BioPAX pathway converted from "Regulation of TLR by endogenous ligand" in the Reactome database. Regulation of TLR by endogenous ligand This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LEFT-TO-RIGHT HMGB1 release from cells This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> hmgb1 HMGB1 Q6P4N5 Reactome DB_ID: 10491685 nucleoplasm GENE ONTOLOGY GO:0005654 UniProt:Q6P4N5 hmgb1 Xenopus tropicalis NCBI Taxonomy 8364 UniProt Q6P4N5 2 EQUAL 215 EQUAL Reactome Database ID Release 82 10491685 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10491685 Reactome R-XTR-266221 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-266221.1 Reactome http://www.reactome.org hmgb1 HC23,45-HMGB1 Q6P4N5 Reactome DB_ID: 10548730 extracellular region GENE ONTOLOGY GO:0005576 23 EQUAL L-cystine (cross-link) MOD MOD:00034 2 EQUAL 215 EQUAL Reactome Database ID Release 82 10548730 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10548730 Reactome R-XTR-6797422 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6797422.1 Reactome Database ID Release 82 10549382 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10549382 Reactome R-XTR-6805981 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6805981.1 High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that under normal conditions binds and bends DNA and facilitates gene transcription. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells to function as an alarmin (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Lamkanfi M et al. 2010; Beyer C et al. 2012; Yang H et al. 2013). Earlier studies reported that HMGB1 did not diffuse out of cells undergoing apoptosis as HMGB1 was found to be tightly associated with the chromatin in apoptotic cells, even when the cell membrane was permeabilized artificially with detergents (Scaffidi P et al. 2002). This finding is in agreement with the general observation that apoptosis does not promote inflammation. However, further work showed that cells that undergo apoptosis do release HMGB1 (Bell CW et al. 2006; Yamada Y et al. 2011; Spencer DM et al. 2014). In human apoptotic cells (acute myeloid leukemia H60, HeLa, Jurkat T lymphocyte, pancreatic carcinoma PANC1 cell lines) HMGB1 was found to translocate into membrane-bound vesicles which are generated and released by cells during apoptosis (Spencer DM et al. 2014; Schiller M et al 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013). 22344226 Pubmed 2012 The extracellular release of DNA and HMGB1 from Jurkat T cells during in vitro necrotic cell death Beyer, Christian Stearns, Nancy A Giessl, Adreas Distler, Jörg H W Schett, Georg Pisetsky, David S Innate Immun 18:727-37 23446148 Pubmed 2013 The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis Yang, Huan Antoine, Daniel J Andersson, Ulf Tracey, Kevin J J. Leukoc. Biol. 93:865-73 10952726 Pubmed 2000 High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes Andersson, U Wang, H Palmblad, K Aveberger, A C Bloom, O Erlandsson-Harris, H Janson, A Kokkola, R Zhang, M Yang, H Tracey, K J J. Exp. Med. 192:565-70 23797067 Pubmed 2013 The multifunctional alarmin HMGB1 with roles in the pathophysiology of sepsis and cancer Diener, Kerrilyn R Al-Dasooqi, Noor Lousberg, Erin L Hayball, John D Immunol. Cell Biol. 91:443-50 21093407 Pubmed 2011 The release of high mobility group box 1 in apoptosis is triggered by nucleosomal DNA fragmentation Yamada, Yoichiro Fujii, Taku Ishijima, Rei Tachibana, Haruki Yokoue, Natsuki Takasawa, Ryoko Tanuma, Sei-ichi Arch. Biochem. Biophys. 506:188-93 18300566 Pubmed 2008 High mobility group box 1 in the pathogenesis of inflammatory and autoimmune diseases Voll, Reinhard E Urbonaviciute, Vilma Herrmann, Martin Kalden, Joachim R Isr. Med. Assoc. J. 10:26-8 23194089 Pubmed 2013 During apoptosis HMGB1 is translocated into apoptotic cell-derived membranous vesicles Schiller, Martin Heyder, Petra Ziegler, Saskia Niessen, Anna Claßen, Laura Lauffer, Anna Lorenz, Hanns-Martin Autoimmunity 46:342-6 16855214 Pubmed 2006 The extracellular release of HMGB1 during apoptotic cell death Bell, Charles W Jiang, Weiwen Reich, Charles F Pisetsky, David S Am. J. Physiol., Cell Physiol. 291:C1318-25 24846056 Pubmed 2014 The expression of HMGB1 on microparticles from Jurkat and HL-60 cells undergoing apoptosis in vitro Spencer, D M Mobarrez, F Wallén, H Pisetsky, D S Scand. J. Immunol. 80:101-10 20802146 Pubmed 2010 Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia Lamkanfi, Mohamed Sarkar, Anasuya Vande Walle, L Vitari, Alberto C Amer, Amal O Wewers, Mark D Tracey, Kevin J Kanneganti, Thirumala-Devi Dixit, Vishva M J Immunol 185:4385-92 14532127 Pubmed 2003 Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion Bonaldi, Tiziana Talamo, Fabio Scaffidi, Paola Ferrera, Denise Porto, Annalisa Bachi, Angela Rubartelli, Anna Agresti, Alessandra Bianchi, Marco E EMBO J. 22:5551-60 12149489 Pubmed 2002 High mobility group box chromosomal protein 1 (HMGB1) is an antibacterial factor produced by the human adenoid Zetterström, Cecilia K Bergman, T Rynnel-Dagöö, Britta Erlandsson Harris, Helena Soder, Olle Andersson, Ulf Boman, Hans G Pediatr. Res. 52:148-54 22293756 Pubmed 2012 HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease Harris, Helena Erlandsson Andersson, Ulf Pisetsky, David S Nat Rev Rheumatol 8:195-202 15331624 Pubmed 2004 Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms Chen, Guoqian Li, Jianhua Ochani, Mahendar Rendon-Mitchell, Beatriz Qiang, Xiaoling Susarla, Seenu Ulloa, Luis Yang, Huan Fan, Saijun Goyert, Sanna M Wang, Ping Tracey, Kevin J Sama, Andrew E Wang, Haichao J. Leukoc. Biol. 76:994-1001 12110890 Pubmed 2002 Release of chromatin protein HMGB1 by necrotic cells triggers inflammation Scaffidi, Paola Misteli, Tom Bianchi, Marco E Nature 418:191-5 inferred from electronic annotation EVIDENCE CODE ECO:0000203 LEFT-TO-RIGHT HMGB1 binds LPS This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LPS Gram Negative Bacterial Lipopolysaccharide lipopolysaccharide Reactome DB_ID: 166005 lipopolysaccharide [ChEBI:16412] lipopolysaccharide lipopolysaccharides LPS ChEBI CHEBI:16412 Reactome Database ID Release 82 166005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166005 Reactome R-ALL-166005 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-166005.4 HC23,45-HMGB1:LPS Reactome DB_ID: 10548736 1 1 Reactome Database ID Release 82 10548736 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10548736 Reactome R-XTR-6801229 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6801229.1 Reactome Database ID Release 82 10548738 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10548738 Reactome R-XTR-6804100 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6804100.1 High mobility group box 1 (HMGB1) is an ubiquitous nuclear protein that is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells in response to infection or injury (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013).<p> HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) to potentiate proinflammatory response (Youn JH et al. 2008, 2011; Wähämaa H et al. 2011; Hreggvidsdottir HS et al. 2009). The activity of HMGB1 depended on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3–) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012).<p>HMGB1 binding to LPS facilitated transfer of LPS to CD14 and enhanced TNFalpha production in human peripheral blood mononuclear cells (PBMCs) (Youn JH et al. 2008). HMGB1 in complex with LPS boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wähämaa H et al. 2011; He ZW et al. 2013).<p> In addition to its ability to act in a synergy with LPS and other ligands, HMGB1 was shown to stimulate cells by direct interaction with innate immune receptors such as TLR4:LY96 (Yang H et al. 2010; Yang H et al. 2015). 20547845 Pubmed 2010 A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release Yang, Huan Hreggvidsdottir, Hulda S Palmblad, Karin Wang, Haichao Ochani, Mahendar Li, Jianhua Lu, Ben Chavan, Sangeeta Rosas-Ballina, Mauricio Al-Abed, Yousef Akira, Shizuo Bierhaus, Angelika Erlandsson-Harris, Helena Andersson, Ulf Tracey, Kevin J Proc. Natl. Acad. Sci. U.S.A. 107:11942-7 22869893 Pubmed 2012 Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release Venereau, Emilie Casalgrandi, Maura Schiraldi, Milena Antoine, Daniel J Cattaneo, Angela De Marchis, Francesco Liu, Jaron Antonelli, Antonella Preti, Alessandro Raeli, Lorenzo Shams, Sara Samadi Yang, Huan Varani, Luca Andersson, Ulf Tracey, Kevin J Bachi, Angela Uguccioni, Mariagrazia Bianchi, Marco E J. Exp. Med. 209:1519-28 22105604 Pubmed 2012 Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1) Yang, Huan Lundbäck, Peter Ottosson, Lars Erlandsson-Harris, Helena Venereau, Emilie Bianchi, Marco E Al-Abed, Yousef Andersson, Ulf Tracey, Kevin J Antoine, Daniel J Mol. Med. 18:250-9 24302816 Pubmed 2013 HMGB1 acts in synergy with lipopolysaccharide in activating rheumatoid synovial fibroblasts via p38 MAPK and NF-κB signaling pathways He, Zheng-Wen Qin, Yang-Hua Wang, Zhi-Wei Chen, Yan Shen, Qian Dai, Sheng-Ming Mediators Inflamm. 2013:596716 21660935 Pubmed 2011 Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model Youn, Ju Ho Kwak, Man Sup Wu, Jie Kim, Eun Sook Ji, Yeounjung Min, Hyun Jin Yoo, Ji-Ho Choi, Ji Eun Cho, Hyun-Soo Shin, Jeon-Soo Eur. J. Immunol. 41:2753-62 23207101 Pubmed 2013 HMGB1 and leukocyte migration during trauma and sterile inflammation Venereau, Emilie Schiraldi, Milena Uguccioni, Mariagrazia Bianchi, Marco E Mol. Immunol. 55:76-82 19811284 Pubmed 2009 Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during apoptosis Urbonaviciute, Vilma Meister, Silke Fürnrohr, Barbara G Frey, Benjamin Gückel, Eva Schett, Georg Herrmann, Martin Voll, Reinhard E Autoimmunity 42:305-7 18354232 Pubmed 2008 High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes Youn, Ju Ho Oh, Young Joo Kim, Eun Sook Choi, Ji Eun Shin, Jeon-Soo J. Immunol. 180:5067-74 16878026 Pubmed 2006 HMGB1 signals through toll-like receptor (TLR) 4 and TLR2 Yu, Man Wang, Haichao Ding, Aihao Golenbock, DT Latz, Eicke Czura, Christopher J Fenton, Matthew J Tracey, Kevin J Yang, Huan Shock 26:174-9 19564572 Pubmed 2009 The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation Hreggvidsdottir, Hulda Sigridur Ostberg, Therese Wähämaa, Heidi Schierbeck, Hanna Aveberger, Ann-Charlotte Klevenvall, Lena Palmblad, Karin Ottosson, Lars Andersson, Ulf Harris, Helena Erlandsson J. Leukoc. Biol. 86:655-62 25559892 Pubmed 2015 MD-2 is required for disulfide HMGB1-dependent TLR4 signaling Yang, Huan Wang, Haichao Ju, Zhongliang Ragab, Ahmed A Lundbäck, Peter Long, Wei Valdes-Ferrer, Sergio I He, Mingzhu Pribis, John P Li, Jianhua Lu, Ben Gero, Domokos Szabo, Csaba Antoine, Daniel J Harris, Helena E Golenbock, Doug T Meng, Jianmin Roth, Jesse Chavan, Sangeeta S Andersson, Ulf Billiar, Timothy R Tracey, Kevin J Al-Abed, Yousef J. Exp. Med. 212:5-14 21871094 Pubmed 2011 High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts Wähämaa, Heidi Schierbeck, Hanna Hreggvidsdottir, Hulda S Palmblad, Karin Aveberger, Anne-Charlotte Andersson, Ulf Harris, Helena Erlandsson Arthritis Res. Ther. 13:R136 LEFT-TO-RIGHT HMGB1 binds LTP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> LTA Lipoteichoic acid Reactome DB_ID: 181015 lipoteichoic acid [ChEBI:28640] lipoteichoic acid ChEBI CHEBI:28640 Reactome Database ID Release 82 181015 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181015 Reactome R-ALL-181015 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-181015.4 HC23,45-HMGB1:LTA Reactome DB_ID: 10548732 1 1 Reactome Database ID Release 82 10548732 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10548732 Reactome R-XTR-6801223 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6801223.1 Reactome Database ID Release 82 10548734 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10548734 Reactome R-XTR-6804099 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6804099.1 Lipoteichoic acid (LTA) is a component of the cell wall of Gram-positive bacteria. LTA induces a toll-like receptor 2 (TLR2)-mediated inflammatory response upon initial binding to coreceptors CD36 and CD14 (Nilsen NJ et al. 2008).<p>High mobility group box protein 1 (HMGB1) is a ubiquitous nuclear protein that under normal conditions binds and bends DNA and facilitates gene transcription. In response to infection or injury, HMGB1 is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013). HMGB1 has been implicated in TLR2-mediated inflammation (Yu M et al. 2006; Park JS et al. 2006). Addition of HMGB1 induced cellular activation and TLR2- and TLR4-mediated NFkappaB-dependent transcription in TLR2- or TLR4-transfected human embryonic kidney-293 (HEK293) cells (Park JS et al. 2006). Mouse Tlr2 was found to associate with immunoprecipitated Hmgb1 from mouse macrophage-like RAW264.7 cell lysates (Park JS et al. 2006). Anti-TLR2 antibodies dose-dependently attenuated HMGB1-induced IL-8 release in TLR2-expressing HEK293 cells and markedly reduced HMGB1 cell surface binding on murine macrophage-like RAW 264.7 cells (Yu M et al. 2006). Moreover, results of ELISA, surface plasmon resonance and native PAGE electrophoretic mobility shift analyses indicated that HMGB1 binds LTA in a concentration-dependent manner and that this binding is inhibited by LBP (Kwak MS et al. 2015). Native PAGE, fluorescence-based transfer and confocal imaging analyses indicated that HMGB1 catalytically disaggregated LTA transfering LTA to CD14. NFkappaB p65 nuclear transmigration, degradation of IkBalpha and reporter assay results demonstrated that NFkappaB activity in HEK293-hTLR2/6 cells was significantly upregulated by a mixture of LTA and soluble CD14 in the presence of HMGB1 (Kwak MS et al. 2015). Furthermore, the production of TNFalpha and IL6 in murine J774A.1 and RAW264.7 cells increased significantly following treatment with a mixture of LTA and HMGB1 compared with treatment with LTA or HMGB1 alone (Kwak MS et al. 2015). Thus, HMGB1 was proposed to play an important role in LTA-mediated inflammation by binding to LTA and transferring LTA to CD14, which is subsequently transferred to TLR2:TLR6 to induce an inflammatory response. 18458151 Pubmed 2008 Cellular trafficking of lipoteichoic acid and Toll-like receptor 2 in relation to signaling: role of CD14 and CD36 Nilsen, NJ Deininger, S Nonstad, U Skjeldal, F Husebye, H Rodionov, D von Aulock, S Hartung, T Lien, E Bakke, O Espevik, T J Leukoc Biol 84:280-91 25660311 Pubmed 2015 HMGB1 Binds to Lipoteichoic Acid and Enhances TNF-α and IL-6 Production through HMGB1-Mediated Transfer of Lipoteichoic Acid to CD14 and TLR2 Kwak, Man Sup Lim, Mihwa Lee, Yong Joon Lee, Hyun Sook Kim, Young Hun Youn, Ju Ho Choi, Ji Eun Shin, Jeon-Soo J Innate Immun 7:405-16 16267105 Pubmed 2006 High mobility group box 1 protein interacts with multiple Toll-like receptors Park, Jong Sung Gamboni-Robertson, Fabia He, Qianbin Svetkauskaite, Daiva Kim, Jae-Yeol Strassheim, Derek Sohn, Jang-Won Yamada, Shingo Maruyama, Ikuro Banerjee, Anirban Ishizaka, Akitoshi Abraham, Edward Am. J. Physiol., Cell Physiol. 290:C917-24 LEFT-TO-RIGHT SFTPA/SFTPD binds TLR2:TLR1 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome SFTPA oligomer, SFTPD oligomer Reactome DB_ID: 10534579 SFTPA oligomer Reactome DB_ID: 10534571 Reactome Database ID Release 82 10534571 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534571 Reactome R-XTR-391092 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-391092.1 SFTPD oligomer Reactome DB_ID: 10534577 Reactome Database ID Release 82 10534577 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534577 Reactome R-XTR-391097 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-391097.1 Reactome Database ID Release 82 10534579 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534579 Reactome R-XTR-391108 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-391108.1 TLR1:TLR2 Reactome DB_ID: 10534592 plasma membrane GENE ONTOLOGY GO:0005886 tlr2 TLR2 A0A803JIX3 Reactome DB_ID: 10534582 UniProt:A0A803JIX3 tlr2 UniProt A0A803JIX3 19 EQUAL 784 EQUAL Reactome Database ID Release 82 10534582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534582 Reactome R-XTR-167992 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-167992.1 1 Converted from EntitySet in Reactome Homologues of TLR1 Reactome DB_ID: 10534590 tlr6 TLR1 A0A6I8PMY8 Reactome DB_ID: 10534584 UniProt:A0A6I8PMY8 tlr6 UniProt A0A6I8PMY8 25 EQUAL 786 EQUAL Reactome Database ID Release 82 10534584 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534584 Reactome R-XTR-6787702 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6787702.1 TLR1 LOC100495326 A0A6I8QWK0 Reactome DB_ID: 10534586 UniProt:A0A6I8QWK0 LOC100495326 UniProt A0A6I8QWK0 25 EQUAL 786 EQUAL Reactome Database ID Release 82 10534586 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534586 Reactome R-XTR-6787702-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6787702-2.1 tlr1 TLR1 A0A6I8SK42 Reactome DB_ID: 10534588 UniProt:A0A6I8SK42 tlr1 UniProt A0A6I8SK42 25 EQUAL 786 EQUAL Reactome Database ID Release 82 10534588 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534588 Reactome R-XTR-6787702-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6787702-3.1 Reactome Database ID Release 82 10534590 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534590 Reactome R-XTR-6787702-4 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6787702-4.1 1 Reactome Database ID Release 82 10534592 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534592 Reactome R-XTR-168946 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-168946.1 SFTPA/SFTPD:TLR2:TLR1 Reactome DB_ID: 10534594 1 1 Reactome Database ID Release 82 10534594 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534594 Reactome R-XTR-5432872 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5432872.1 Reactome Database ID Release 82 10534596 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10534596 Reactome R-XTR-5432814 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5432814.1 The lung surfactant proteins SP-A (also known as SFTPA) and SP-D (SFTPD) have been implicated in the regulation of pulmonary host defense and inflammation. SP-A and SP-D were found to bind to the recombinant soluble form of extracellular TLR2 domain (TLR2) via its C-terminal carbohydrate recognition domain (CRD) in a Ca(2+)-dependent manner (Murakami S et al. 2002; Ohya M et al. 2006). SP-A downregulated TLR2-mediated signaling and tumor necrosis factor alpha (TNFalpha) secretion in TLR2-transfected human embryonic kidney 293 (HEK293) cells upon stimulation with TLR2 ligands such as fungal cell surface component zymosan or bacterial peptidoglycan (PGN) (Murakami S et al. 2002; Sato M et al. 2003). Similarly, SP-A significantly reduced PGN-elicited TNFalpha secretion by human leukemic monocyte lymphoma U937 cell line and rat alveolar macrophages (Murakami S et al. 2002). In primary human monocyte-derived macrophage SP-A regulated TLR2 and TLR4 activity by diminishing proinflammatory cytokine production as the result of a decreased phosphorylation of a key regulator of NFkB, IkBalpha. Nuclear translocation of NFkB-p65 (RELA) was also inhibited (Henning LN et al. 2008). SP-A downregulated kinases upstream of IkBalpha by decreasing the phosphorylation of Akt and MAPKs in response to either LPS (TLR4 ligand) or Pam3Cys (TLR2 ligand) (Henning LN et al. 2008). In addition, SP-A upregulated surface protein expression of TLR2 on macrophages, while it did not affect TLR4 surface expression. The increased TLR2 expression is thought to enhance pathogen recognition by TLR2, while SP-A mediated inhibition of TLR signaling may protect from an overreactive inflammatory response (Henning LN et al. 2008). 16213021 Pubmed 2006 Surfactant proteins SP-A and SP-D: structure, function and receptors Kishore, U Greenhough, TJ Waters, P Shrive, AK Ghai, R Kamran, MF Bernal, AL Reid, KB Madan, T Chakraborty, T Mol Immunol 43:1293-315 16834340 Pubmed 2006 Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide Ohya, Madoka Nishitani, Chiaki Sano, Hitomi Yamada, Chieko Mitsuzawa, Hiroaki Shimizu, Takeyuki Saito, Tsuyoshi Smith, Kelly Crouch, Erika Kuroki, Yoshio Biochemistry 45:8657-64 12817025 Pubmed 2003 Direct binding of Toll-like receptor 2 to zymosan, and zymosan-induced NF-kappa B activation and TNF-alpha secretion are down-regulated by lung collectin surfactant protein A Sato, Morihito Sano, Hitomi Iwaki, Daisuke Kudo, Kazumi Konishi, Masanori Takahashi, Hiroki Takahashi, Toru Imaizumi, Hitoshi Asai, Yasufumi Kuroki, Yoshio J. Immunol. 171:417-25 18523248 Pubmed 2008 Pulmonary surfactant protein A regulates TLR expression and activity in human macrophages Henning, Lisa N Azad, Abul K Parsa, Kishore V L Crowther, Joy E Tridandapani, Susheela Schlesinger, Larry S J. Immunol. 180:7847-58 11724772 Pubmed 2002 Surfactant protein A inhibits peptidoglycan-induced tumor necrosis factor-alpha secretion in U937 cells and alveolar macrophages by direct interaction with toll-like receptor 2 Murakami, Seiji Iwaki, Daisuke Mitsuzawa, Hiroaki Sano, Hitomi Takahashi, Hiroki Voelker, DR Akino, Toyoaki Kuroki, Yoshio J. Biol. Chem. 277:6830-7 LEFT-TO-RIGHT oxPL binds CD14 This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> A0A6I8PVH6 CD14(20-345) Reactome DB_ID: 10483324 UniProt:A0A6I8PVH6 UniProt A0A6I8PVH6 20 EQUAL 345 EQUAL Reactome Database ID Release 82 10483324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10483324 Reactome R-XTR-166025 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-166025.1 oxidised phospholipid oxidized phospholipids Reactome DB_ID: 2186967 oxidised phospholipid [ChEBI:60156] oxidised phospholipid oxidised phospholipids OxPL OxPLs oxidized phospholipids oxidized phospholipid ChEBI CHEBI:60156 Reactome Database ID Release 82 2186967 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2186967 Reactome R-ALL-2186967 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2186967.3 CD14:oxPL Reactome DB_ID: 10555040 1 1 Reactome Database ID Release 82 10555040 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10555040 Reactome R-XTR-8869691 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-8869691.1 Reactome Database ID Release 82 10555042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10555042 Reactome R-XTR-8869694 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-8869694.1 The generation of reactive oxygen species is a central feature of inflammation that results in the oxidation of host phospholipids. Endogenously formed oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit TLR4- & TLR2-mediated signaling induced by bacterial lipopeptide or lipopolysaccharide (LPS) in various human cells (Bochkov VN et al., 2002; von Schlieffen E et al., 2009). Oxidized phospholipids were found to bind LPS binding protein (LBP) and soluble CD14 suggesting that the binding prevented recognition of LPS by these proteins thus preventing recognition of LPS and activation of TLR4 (Erridge C et al., 2008; von Schlieffen E et al., 2009). In addition, oxPAPC protected mice treated with a lethal dose of LPS (Bochkov VN et al., 2002). Thus, oxidized phospholipids may function as a negative feedback to blunt innate immune responses. 12214235 Pubmed 2002 Protective role of phospholipid oxidation products in endotoxin-induced tissue damage Bochkov, Valery N Kadl, Alexandra Huber, Joakim Gruber, Florian Binder, Bernd R Leitinger, Norbert Nature 419:77-81 19112167 Pubmed 2009 Multi-hit inhibition of circulating and cell-associated components of the toll-like receptor 4 pathway by oxidized phospholipids von Schlieffen, Elena Oskolkova, Olga V Schabbauer, Gernot Gruber, Florian Bluml, Stephan Genest, Melinda Kadl, Alexandra Marsik, Claudia Knapp, Sylvia Chow, Jesse Leitinger, Norbert Binder, Bernd R Bochkov, Valery N Arterioscler. Thromb. Vasc. Biol. 29:356-62 12775576 Pubmed 2003 Specific phospholipid oxidation products inhibit ligand activation of toll-like receptors 4 and 2 Walton, Kimberly A Cole, Amy L Yeh, Michael Subbanagounder, Ganesamoorthy Krutzik, Stephan R Modlin, Robert L Lucas, Robert M Nakai, Junko Smart, Eric J Vora, Deven K Berliner, Judith A Arterioscler. Thromb. Vasc. Biol. 23:1197-203 18559343 Pubmed 2008 Oxidized phospholipid inhibition of toll-like receptor (TLR) signaling is restricted to TLR2 and TLR4: roles for CD14, LPS-binding protein, and MD2 as targets for specificity of inhibition Erridge, Clett Kennedy, Simon Spickett, Corinne M Webb, David J J. Biol. Chem. 283:24748-59 LEFT-TO-RIGHT oxPL binds LBP This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> Converted from EntitySet in Reactome Homologues of LBP Reactome DB_ID: 10482283 LBP LOC116408073 A0A803J315 Reactome DB_ID: 10482269 UniProt:A0A803J315 LOC116408073 UniProt A0A803J315 26 EQUAL 481 EQUAL Reactome Database ID Release 82 10482269 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482269 Reactome R-XTR-166010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-166010.1 LBP bpi.4 A0A803JPY4 Reactome DB_ID: 10482273 UniProt:A0A803JPY4 bpi.4 UniProt A0A803JPY4 26 EQUAL 481 EQUAL Reactome Database ID Release 82 10482273 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482273 Reactome R-XTR-166010-2 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-166010-2.1 LBP A0A803K8V6 Reactome DB_ID: 10482277 UniProt:A0A803K8V6 UniProt A0A803K8V6 26 EQUAL 481 EQUAL Reactome Database ID Release 82 10482277 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482277 Reactome R-XTR-166010-3 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-166010-3.1 LBP MGC108117 Q5FWR5 Reactome DB_ID: 10482281 UniProt:Q5FWR5 MGC108117 UniProt Q5FWR5 26 EQUAL 481 EQUAL Reactome Database ID Release 82 10482281 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482281 Reactome R-XTR-166010-4 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-166010-4.1 Reactome Database ID Release 82 10482283 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10482283 Reactome R-XTR-166010-5 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-166010-5.1 LBP:oxPL Reactome DB_ID: 10555036 1 1 Reactome Database ID Release 82 10555036 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10555036 Reactome R-XTR-8869676 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-8869676.1 Reactome Database ID Release 82 10555038 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10555038 Reactome R-XTR-8869683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-8869683.1 Antibacterial defence involves activation of neutrophils that generate reactive oxygen species (ROS) capable of killing bacteria. The ROS production results in the oxidation of host phospholipids. Endogenously formed oxidized phospholipids, such as 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (OxPAPC), have been shown to inhibit TLR4- & TLR2-mediated signaling induced by bacterial lipopeptide or lipopolysaccharide (LPS) in various human cells (Bochkov VN et al., 2002; von Schlieffen E et al., 2009). Oxidized phospholipids were found to bind LPS binding protein (LBP) and soluble CD14 suggesting that the binding prevented recognition of LPS by these proteins thus preventing recognition of LPS and activation of TLR4 (Erridge C et al., 2008; von Schlieffen E et al., 2009). In addition, oxPAPC protected mice treated with a lethal dose of LPS (Bochkov VN et al., 2002). Thus, oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Reactome Database ID Release 82 10568742 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10568742 Reactome R-XTR-5686938 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-5686938.1 Diverse molecules of host-cell origin may serve as endogenous ligands of Toll-like receptors (TLRs) (Erridge C 2010; Piccinini AM & Midwood KS 2010). These molecules are known as damage-associated molecular patterns (DAMPs). DAMPs are immunologically silent in healthy tissues but become active upon tissue damage during both infectious and sterile insult. DAMPs are released from necrotic cells or secreted from activated cells in response to tissue damage to mediate tissue repair by promoting inflammatory responses. However, DAMPs have also been implicated in the pathogenesis of many inflammatory and autoimmune diseases, including rheumatoid arthritis (RA), cancer, and atherosclerosis. The mechanism underlying the switch from DAMPs that initiate controlled tissue repair, to those that mediate chronic, uncontrolled inflammation is still unclear. Recent evidence suggests that an abnormal increase in protein citrullination is involved in disease pathophysiology (Anzilotti C et al. 2010; Sanchez-Pernaute O et al. 2013; Sokolove J et al. 2011; Sharma P et al. 2012). Citrullination is a post-translational modification event mediated by peptidyl-arginine deaminase enzymes which catalyze the deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. 20954191 Pubmed 2011 Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor Sokolove, Jeremy Zhao, Xiaoyan Chandra, Piyanka E Robinson, William H Arthritis Rheum. 63:53-62 20629986 Pubmed 2010 Endogenous toll-like receptor ligands and their biological significance Yu, Li Wang, Liantang Chen, Shangwu J. Cell. Mol. Med. 14:2592-603 25391648 Pubmed 2014 Complexity of danger: the diverse nature of damage-associated molecular patterns Schaefer, Liliana J. Biol. Chem. 289:35237-45 23028349 Pubmed 2012 Citrullination of histone H3 interferes with HP1-mediated transcriptional repression Sharma, Priyanka Azebi, Saliha England, Patrick Christensen, Tove Møller-Larsen, Anné Petersen, Thor Batsché, Eric Muchardt, Christian PLoS Genet. 8:e1002934 20179153 Pubmed 2010 Endogenous ligands of TLR2 and TLR4: agonists or assistants? Erridge, Clett J. Leukoc. Biol. 87:989-99 19540364 Pubmed 2010 Peptidylarginine deiminase 4 and citrullination in health and disease Anzilotti, Consuelo Pratesi, Federico Tommasi, Cristina Migliorini, Paola Autoimmun Rev 9:158-60 23234648 Pubmed 2013 Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts Sanchez-Pernaute, Olga Filkova, Maria Gabucio, Antonio Klein, Martin Maciejewska-Rodrigues, Hanna Ospelt, Caroline Brentano, Fabia Michel, Beat A Gay, Renate E Herrero-Beaumont, Gabriel Gay, Steffen Neidhart, Michel Juengel, Astrid Ann. Rheum. Dis. 72:1400-6 20706656 Pubmed 2010 DAMPening inflammation by modulating TLR signalling Piccinini, A M Midwood, K S Mediators Inflamm. 2010: