PAR1 and PAR2 modulate TLR3-dependent expression of IFN-β in CFs. CVB3 infection of CFs leads to the release of ssRNA and the replication intermediate dsRNA into the cytosol. These foreign nucleic acids are recognized by TLR3 in endosomes and the cytoplasmic PRRs retinoic acid–inducible gene I (RIG-I) and melanoma differentiated gene 5 (MDA5). The TLR3-IFN-β pathway plays a central role in the innate immune response to CVB3 infection. Activation of PAR1 by TF-dependent generation of thrombin and MMP13 enhances TLR3-dependent activation of IRF3 and induction of IFN-β but suppresses TLR3-dependent activation of NF-κB and TNF-α expression. In contrast, activation of PAR2, possibly by FXa and/or tryptase, inhibits TLR3-dependent induction of IFN-β expression but enhances TLR3-dependent induction of TNF-α.