The contribution of PARs to inflammation and immunity to fungi

During inflammation, host- and microbial-derived proteases trigger the activation of protease-activated receptors (PARs), a family of G-protein-coupled receptors. We report here that activation of Toll-like receptors (TLRs) by fungi unmasks an essential and divergent role for PAR 1 and PAR 2 in downstream signaling and inflammation. TLRs activated PARs and triggered distinct signal transduction pathways involved in inflammation and immunity to Candida albicans and Aspergillus fumigatus. Inflammation was promoted by PAR 1 and PAR 2 activation in response to Candida and by PAR 2 inhibition in response to Aspergillus. This occurred by TLR regulation of PAR signaling, with TLR2 promoting PAR 1 activity, and TLR4 suppressing PAR 2 activity. Thus, tissue injury and pathogens induce signals that are integrated at the level of distinct TLR/PAR-dependent pathways, the exploitation or subversion of which contributes to divergence in microbial promotion of inflammatory response.