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P94 TLR7 and TLR8 differentially activate the IRF and NF-kB pathways in specific cell types to promote inflammation
  1. Andrew T Bender,
  2. Evgeni Tzvetkov,
  3. Albertina Pereira,
  4. Siddha Kasar,
  5. Melinda Przetak,
  6. Shinji Okitsu and
  7. Jaromir Vlach
  1. Immunology, EMD Serono Research and Development Institute, Billerica, USA


Background TLR7 and TLR8 are pattern recognition receptors that reside in the endosome and are activated by ssRNA molecules. TLR7 and TLR8 participate in the anti-viral defense response but their aberrant activation has also been implicated as a driver of autoimmune diseases such as lupus. The receptors have slightly different ligand binding specificities and cellular expression patterns suggesting they have non-redundant specialized roles. How the roles of TLR7 and TLR8 differ in driving disease may be determined by which cell types express the TLRs and how they respond to activation of each.

Methods To delineate the differential effects of TLR7 or TLR8 activation we used gene expression analysis and intracellular cytokine staining to characterize changes induced by TLR specific agonists in different immune cell types. Anti-IFNR antibody treatment was also used in whole blood and lupus mice to further define which responses are a direct consequence of TLR7/8 activation and which are secondary responses driven by Type I interferon or cytokines produced subsequent to the primary response.

Results It was found that the IRF and NF-kB pathways are differentially activated downstream of the TLRs in various cell types. The differential expression and activity of TLR7 vs TLR8 was notable when comparing different DC populations, monocytes, and neutrophils. TLR7 was more biased toward activation of IRF responses while TLR8 activation resulted in stronger NF-kB signaling. The anti-IFNR antibody studies showed that inhibiting IFN activity can block secondary IFN-induced gene expression changes downstream of TLR7/8 activation, but not NF-kB-regulated genes induced directly by TLR7/8 activation at early timepoints.

Conclusions In summary, these results elucidate the ways in which TLR7 and TLR8 regulate immunity and how their activation may shape an immune response. The results also have implications for selecting strategies for treating autoimmune diseases driven by TLR7/8 activation.

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