TLR2 activation of TRIF controls both early inflammatory and late tolerance responses to Borrelia burgdorferi (180.11)

Abstract

Abstract TRIF is an adaptor molecule important in transducing signals from intracellularly signaling toll-like receptors (TLRs) 3 and 4, but not other TLR family members. Recently, TLR2 was found to signal from intracellular compartments. Using a synthetic ligand for TLR2/1 heterodimers as well as the bacterium Borrelia burgdorferi, which causes Lyme disease and is a strong activator of TLR2/1, we found that, contrary to current dogma, TLR2 signaling can utilize TRIF. Unlike TRIF signaling by other TLRs, TLR2-mediated TRIF signaling is dependent on the presence of another adaptor molecule, MyD88. However, unlike MyD88, TRIF deficiency does not result in diminished control of infection with B. burgdorferi. This appears to be due to the effects of MyD88 on phagocytosis via scavenger receptors such as MARCO which are not affected by the loss of TRIF. Although TRIF deficiency is associated with a decrease in pro-inflammatory cytokine induction in vitro, in an animal model of B. burgdorferi infection, loss of TRIF resulted in an increase in IL-6. In vitro studies mimicking longer exposures to B. burgdorferi show that TRIF mediates tolerance to the organism by suppressing pro-inflammatory cytokines disproportionately to anti-inflammatory cytokines in response to long term stimulation. Our studies suggest a dual role for TRIF in early and late TLR2 responses to infectious organisms.