Poster Presentation Lorne Infection and Immunity 2013

The TLR family member RP105 mediates mycobacteria-induced macrophage cytokine responses independent of canonical TLR signalling (#105)

Chien-Hsiung Yu 1 , Andreas Puyskens 1 , Antje Blumenthal 1
  1. University of Queensland, Brisbane, QLD, Australia

RP105 is a member of the Toll-like receptor (TLR) family that has been reported to facilitate B cell proliferation but limit LPS-induced cytokine production by macrophages and dendritic cells. We recently identified a novel function for RP105 in promoting macrophage cytokine responses during infection with pathogenic mycobacteria. RP105-/- macrophages showed reduced cytokine responses upon infection with Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis, BCG. Our data indicate that RP105 physically interacts with TLR2 and that RP105 and TLR2 are required for optimal macrophage activation by Mtb. The 19 kDa lipoprotein of Mtb and a synthetic hexadeca-lipopeptide analogue, both TLR2 agonists, induced TNF release in a manner dependent on both TLR2 and RP105. However, we also obtained evidence suggesting that RP105 is not simply facilitating activation of classical TLR2 signalling events. Mycobacteria-induced activation of the NF-kB and MAP kinase cascades remained intact in RP105-/- but not TLR2-/- macrophages. In addition, not all TLR2 agonists including Pam3CSK4 (TLR2/1) and FSL-1 (TLR2/6) required RP105 for optimal cytokine production by macrophages. The mRNA expression for many inflammatory genes, the number of TNF expressing cells as well as the level of cell-associated TNF protein were comparable in WT and RP105-/- macrophages upon mycobacterial infection. These observations suggest a role for RP105 in regulating mycobacteria-induced TNF release from macrophages. Taken together, our data identify RP105 an accessory molecule for TLR2 and as part of the host receptor complex for mycobacterial ligands that might foster macrophage activation independent of classical TLR signalling.

Support: NHMRC, University of Queensland