Mycobacterial infections, in particular tuberculosis, remain a significant public health concern worldwide. Macrophages are the major host cells for pathogenic mycobacteria and play a central role in containing the pathogen and initiating inflammatory cytokine responses. Radioprotective 105 kDa (RP105) is a member of the Toll-like receptor (TLR) family that has been demonstrated to facilitate B cell proliferation but limit LPS-driven cytokine production by antigen-presenting cells. Our group recently identified a novel role for RP105 in promoting macrophage cytokine production during infection with pathogenic mycobacteria. RP105-deficient macrophages showed reduced cytokine secretion upon infection with Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis, BCG. While we previously observed physical and functional interactions between RP105 and TLR2, we now show that canonical TLR signalling such as activation of MAP kinase and NF-κB signalling remained intact in RP105-deficient macrophages during mycobacterial infection. Furthermore, mycobacteria-induced mRNA and protein expression of cytokines such as TNF and IL-6 were comparable in WT and RP105-deficent macrophages. In contrast, RP105-deficient macrophages infected with mycobacteria displayed reduced cell surface-associated TNF suggesting diminished TNF trafficking in these cells. We further observed that PI3K signalling is significantly inhibited in RP105-/- macrophages and identified that PI3Kδ activity is involved in regulating mycobacteria-induced macrophage TNF secretion downstream of RP105. Furthermore, expression of components of the cytokine trafficking machinery were found to be significantly diminished in RP105-/- macrophages infected with mycobacteria. Taken together, our observations identify RP105 as an integral part of the innate immune receptor complex for pathogenic mycobacteria that contributes to macrophage responses by regulating trafficking of TNF and possibly other cytokines.
Support: NHMRC