title: Neutralization of pro-inflammatory monocytes by targeting TLR2 dimerization ameliorates colitis.
abstract: Monocytes have emerged as critical driving force of acute inflammation. Here, we show that inhibition of Toll-like receptor 2(TLR2) dimerization by a TLR2 transmembrane peptide (TLR2-p) ameliorated DSS-induced colitis by interfering specifically with the activation of Ly6C(+) monocytes without affecting their recruitment to the colon. We report that TLR2-p directly interacts with TLR2 within the membrane, leading to inhibition of TLR2-TLR6/1 assembly induced by natural ligands. This was associated with decreased levels of extracellular signal-regulated kinases (ERK) signaling and reduced secretion of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-23, IL-12, and IL-1β. Altogether, our study provides insights into the essential role of TLR2 dimerization in the activation of pathogenic pro-inflammatory Ly6C(hi) monocytes and suggests that inhibition of this aggregation by TLR2-p might have therapeutic potential in the treatment of acute gut inflammation.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Liraz
authors.initials: L
authors.lastname: Shmuel-Galia
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Tegest
authors.initials: T
authors.lastname: Aychek
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Avner
authors.initials: A
authors.lastname: Fink
authors.affiliation: Department of Biological Services, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Porat
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Batya
authors.initials: B
authors.lastname: Zarmi
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Biana
authors.initials: B
authors.lastname: Bernshtein
authors.affiliation: Department of Veterinary Resources, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Brenner
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel s.jung@weizmann.ac.il yechiel.shai@weizmann.ac.il.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel s.jung@weizmann.ac.il yechiel.shai@weizmann.ac.il.
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Shai
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000032:analysis; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D003106:Colon / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D016130:Immunophenotyping; D020935:MAP Kinase Signaling System; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology*; D055503:Protein Multimerization; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; D016207:Cytokines; C494192:Ly-6C antigen, mouse; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6
keywords: TLR2; Toll‐like receptor; colitis; monocytes