Targeting TLR2 Transsmembrane Domain Dimerization on Pro-Inflammatory Monocytes Ameliorates Acute Colitis - The Israel Society for Biochemistry & Molecular Biology (ISBMB) Abstract Submission Form

Liraz Shmuel-Galia ¹ Tegest Aychek ² Avner Fink ¹ Ziv Porat ³ Batya Zarmi ¹ Ori Brenner ⁴ Steffen Jung ² Yechiel Shai ¹

¹Departments of Biological Chemistry, Weizmann Institute of Science, Rehovot
²Departments of Immunology, Weizmann Institute of Science, Rehovot
³Departments of Biological Services, Weizmann Institute of Science, Rehovot
⁴Departments of Veterinary Resources, Weizmann Institute of Science, Rehovot

Toll-like receptors (TLR) are membrane pattern recognition receptors that recognize a wide range of microbial products. TLR activation by certain ligands induces the critical formation of TLR dimers with unique specificities. TLR2 dimerizes, for instance, with TLR6 and TLR1 upon binding to di- and tri-acylated lipoproteins, respectively (Botos, I. et al., (2011) Structure 19, 447-459). During acute and chronic inflammation, TLR engagement by commensal-derived microbial products triggers the production of pro-inflammatory agents.

Monocytes have emerged as a critical driving force of acute inflammation. Interestingly, Ly6C^hi monocytes that enter inflamed gut tissue up-regulate expression of TLR2, TLR6 and NOD2 (Zigmond et al. (2012) Immunity 37, 1076-1090) that are critical for their ability to produce pro-inflammatory cytokines. This suggests that Ly6C^himonocytes cells might play a central role in the TLR2 heterodimer-mediated inflammatory tissue reaction in the context of UC.

Here we report a novel strategy to target TLR2 activation by inhibiting TLR2 dimerization with the help of a TLR2 transmembrane domain peptide, TLR2-p (Fink, A. et al., ((2013) J Immunol 190, 6410-6422). Intra-peritoneal TLR2-p injections significantly 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, TLR6 and TLR1 within the membrane, leading to inhibition of TLR2 assembly induced by natural ligands. This was accompanied by decreased levels of pro-inflammatory cytokines, such as 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^himonocytes and highlights the potential of TLR2-p treatment and blockade of TLR dimerization, as a novel therapeutic modality for acute gut inflammation.