{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTLR6 is a conserved innate immune receptor that primarily functions as a co‐receptor with TLR2 to detect distinct microbial and endogenous ligands. In several studies, TLR6 has been shown to form heterodimers with TLR2, thereby enabling the recognition of diacylated lipoproteins from bacteria such as Mycoplasma pneumoniae and Lyme disease–causing Borrelia, as well as lipoprotein components from organisms like Wolbachia. In cell‐based assays, expression of TLR6 alongside TLR2 is essential for NF‑κB activation in response to these ligands, a response that is not observed when TLR2 is expressed alone."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in ligand recognition, TLR6 contributes to the modulation of inflammatory signaling. Engagement of TLR2/TLR6 complexes triggers cascades that culminate in cytokine production via NF‑κB activation, and these responses can be modulated by the lipid composition of the environment. For example, saturated fatty acids can promote whereas polyunsaturated fatty acids inhibit NF‑κB activation in cells co‐expressing TLR2 with TLR6. Moreover, studies employing blocking monoclonal antibodies have demonstrated that cell-surface expression of TLR6 on monocytes, dendritic cells, and neutrophils is critical for the recognition of diacylated lipopeptides and peptidoglycan. The impact of naturally occurring TLR6 polymorphisms on NF‑κB signaling further highlights its regulatory role in innate responsiveness."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, alterations in TLR6-mediated signaling have been implicated in the pathogenesis of several human diseases. For instance, deletion of TLR6 in Schwann cells abolishes the formation of lipid droplets—a process linked to the survival of Mycobacterium leprae in nerve tissues—underscoring TLR6’s importance in host–pathogen interactions in leprosy. Similarly, dengue virus non-structural protein 1 (NS1) has been found to activate cytokine release via TLR2/TLR6, and in experimental models, TLR6 deficiency confers improved survivability during dengue infection. Altered expression patterns of TLR6 in inflammatory conditions such as Behcet’s disease suggest that its dysregulated activity may also influence auto-inflammatory processes. Together, these findings indicate that TLR6 not only expands the ligand recognition spectrum in partnership with TLR2 but also plays a critical role in tailoring inflammatory responses during infection and sterile inflammatory diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Joo Y Lee, Ling Zhao, Hyung S Youn, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Saturated fatty acid activates but polyunsaturated fatty acid inhibits Toll-like receptor 2 dimerized with Toll-like receptor 6 or 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M312990200"}], "href": "https://doi.org/10.1074/jbc.M312990200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14966134"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14966134"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "K Tantisira, W T Klimecki, R Lazarus, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor 6 gene (TLR6): single-nucleotide polymorphism frequencies and preliminary association with the diagnosis of asthma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Immun (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.gene.6364096"}], "href": "https://doi.org/10.1038/sj.gene.6364096"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15266299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15266299"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yoshiya Nakao, Kenji Funami, Satomi Kikkawa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Surface-expressed TLR6 participates in the recognition of diacylated lipopeptide and peptidoglycan in human cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.174.3.1566"}], "href": "https://doi.org/10.4049/jimmunol.174.3.1566"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15661917"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15661917"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nicolas W J Schröder, Isabel Diterich, Antje Zinke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.175.4.2534"}], "href": "https://doi.org/10.4049/jimmunol.175.4.2534"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16081826"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16081826"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Takashi Shimizu, Yutaka Kida, Koichi Kuwano "}, {"type": "b", "children": [{"type": "t", "text": "A dipalmitoylated lipoprotein from Mycoplasma pneumoniae activates NF-kappa B through TLR1, TLR2, and TLR6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.175.7.4641"}], "href": "https://doi.org/10.4049/jimmunol.175.7.4641"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16177110"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16177110"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Sandra Kesh, Nana Yaa Mensah, Paolo Peterlongo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TLR1 and TLR6 polymorphisms are associated with susceptibility to invasive aspergillosis after allogeneic stem cell transplantation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann N Y Acad Sci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1196/annals.1358.012"}], "href": "https://doi.org/10.1196/annals.1358.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16461792"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16461792"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Martha Triantafilou, Frederick G J Gamper, Rowenna M Haston, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intracellular targeting."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M602794200"}], "href": "https://doi.org/10.1074/jbc.M602794200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16880211"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16880211"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Katja Farhat, Sabine Riekenberg, Holger Heine, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Leukoc Biol (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1189/jlb.0807586"}], "href": "https://doi.org/10.1189/jlb.0807586"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18056480"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18056480"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Joseph D Turner, R Stuart Langley, Kelly L Johnston, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Wolbachia lipoprotein stimulates innate and adaptive immunity through Toll-like receptors 2 and 6 to induce disease manifestations of filariasis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M901528200"}], "href": "https://doi.org/10.1074/jbc.M901528200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19458089"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19458089"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Cameron R Stewart, Lynda M Stuart, Kim Wilkinson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.1836"}], "href": "https://doi.org/10.1038/ni.1836"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20037584"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20037584"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Alexander Panda, Feng Qian, Subhasis Mohanty, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.0901022"}], "href": "https://doi.org/10.4049/jimmunol.0901022"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20100933"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20100933"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "P Selvaraj, M Harishankar, Brijendra Singh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Toll-like receptor and TIRAP gene polymorphisms in pulmonary tuberculosis patients of South India."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Tuberculosis (Edinb) (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.tube.2010.08.001"}], "href": "https://doi.org/10.1016/j.tube.2010.08.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20797905"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20797905"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Katherine A Mattos, Viviane G C Oliveira, Heloisa D'Avila, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TLR6-driven lipid droplets in Mycobacterium leprae-infected Schwann cells: immunoinflammatory platforms associated with bacterial persistence."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1101344"}], "href": "https://doi.org/10.4049/jimmunol.1101344"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21813774"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21813774"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Jincheng Chen, Mary Mah-Lee Ng, Justin Jang Hann Chu "}, {"type": "b", "children": [{"type": "t", "text": "Activation of TLR2 and TLR6 by Dengue NS1 Protein and Its Implications in the Immunopathogenesis of Dengue Virus Infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Pathog (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.ppat.1005053"}], "href": "https://doi.org/10.1371/journal.ppat.1005053"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26226614"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26226614"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Ying-Hsien Huang, Sung-Chou Li, Lien-Hung Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identifying genetic hypomethylation and upregulation of Toll-like receptors in Kawasaki disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.14497"}], "href": "https://doi.org/10.18632/oncotarget.14497"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28061462"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28061462"}]}]}]}