Role of SLC11A1 (formerly NRAMP1) in regulation of signal transduction induced by Toll-like receptor 7 ligands

Modulation of immune responses using Toll-like receptor (TLR) ligands is fast becoming one of the main new approaches for the treatment of infectious and allergic diseases. Characterizing the role of genetic factors in modulating responses to these ligands will be crucial in determining the efficacy of a particular treatment. Our previous findings have shown that treatment of Mycobacterium bovis BCG infection with a synthetic TLR7 ligand resulted in a reduction of the splenic bacterial load only in mice carrying a wild-type allele of Nramp1. To understand further how natural resistance-associated macrophage protein 1 (NRAMP1) modulates responses to TLR7 ligands, we have analysed various important TLR7 signal transduction events in macrophage cell lines derived from B10.A(Nramp1(r)) and B10.A(Nramp1(-/-)) mice. The Nramp1 genotype did not affect TLR7 receptor expression, ligand uptake or intracellular processing. Following TLR7 ligand stimulation, p38 mitogen-activated protein kinase (MAPK) activation was significantly reduced in B10A.Nramp1(-/-) macrophages compared with B10A.Nramp1(r) cells. Interestingly, levels of protein kinase C zeta (PKC zeta) activation were also found to be lower in B10A.Nramp1(-/-) macrophages and inhibition of this kinase in B10A.Nramp1(r) cells led to a reduction in cytokine production. Taken together, the data demonstrate a role for NRAMP1 in modulating p38 MAPK and PKC zeta activity, which leads to reduced cytokine induction by TLR7 ligands.