Anti-TLR2 monoclonal antibody [APC]

Escherichia coli (E. coli) is a common conditional pathogen that is associated with a variety of infections in humans and animals. Although there are increasing reports regarding the infection of E. coli to domestic animals and poultry, the infection of E. coli in lambs is relatively less reported, especially on meningoencephalitis. Here, we reported the isolation of an E. coli strain designated as NMGCF-19 from lambs characterized with severe diarrhea and neurological disorder, and demonstrated that NMGCF-19 as the causative agent has the ability to disrupt the blood-brain barrier (BBB) to cause the meningoencephalitis using a mouse model. Investigation on the mechanism regarding the NMGCF-19-related meningoencephalitis revealed a significant decreased expression of ZO-1 and occludin in mouse brain tissue in comparison with the control mice. Moreover, infection of NMGCF-19 increased the expression of proinflammatory cytokines TNF-alpha, IL-6, IL-1 beta and IL-18, up-regulated HMGB1 level, and activated TLR2/TLR4/MyD88 and NLRP3 inflammasome pathways. These findings indicated that NMGCF-19 likely invades the brain tissue by disrupting the tight junction (TJ) architecture and causes the meningoencephalitis via increasing inflammatory response and activating TLR2/TLR4/MyD88 and NLRP3 inflammasome pathways.

Toll-like receptors (TLRs) build the first barrier in the innate immune response and therefore represent promising targets for the modulation of inflammatory processes. Recently, the pyrogallol-containing TLR2 antagonists CU-CPT22 and MMG-11 were reported; however, their 1,2,3-triphenol motif renders them highly susceptible to oxidation and excludes them from use in extended experiments under aerobic conditions. Therefore, we have developed a set of novel TLR2 antagonists (1-9) based on the systematic variation of substructures, linker elements, and the hydrogen-bonding pattern of the pyrogallol precursors by using chemically robust building blocks. The novel series of chemically stable and synthetically accessible TLR2 antagonists (1-9) was pharmacologically characterized, and the potential binding modes of the active compounds were evaluated structurally. Our results provide new insights into structure-activity relationships and allow rationalization of structural binding characteristics. Moreover, they support the hypothesis that this class of TLR ligands bind solely to TLR2 and do not directly interact with TLR1 or TLR6 of the functional heterodimer. The most active compound from this series (6), is chemically stable, nontoxic, TLR2-selective, and shows a similar activity with regard to the pyrogallol starting points, thus indicating the variability of the hydrogen bonding pattern.