MAP kinase phosphatase 2 (MKP-2) regulates the innate immune response to influenza infection (INM8P.436)

Abstract

Abstract MAP kinase phosphatases (MKP) are major negative regulators of MAP kinases and are pivotal in the regulation of immune responses. As one member of MKP protein family, MKP-2 has been shown critically regulate p38 and JNK MAP Kinases in response to LPS stimulation in macrophages. While MKP-2 KO mice are more susceptible to intracellular parasite challenge, little is known about the role of MKP-2 in the innate immune response to viral infections. To investigate the role of MKP-2 in innate immune response against influenza, wild type (WT) and MKP-2 knockout (KO) mice were intranasally inoculated with sub-lethal dosage of A/Putero Rico/8/34 (PR8, H1N1) viruses. We found that viral titers in the lung of MKP-2 KO mice are significantly lower on day 3 and day 5 post-infection than those in the lung of WT mice. Correspondingly, the anti-viral cytokines IFN-α and IFN-β were higher in bronchoalveolar lavage fluid from MKP-2 KO mice compared with WT mice. Primary macrophages and dendritic cells from MKP-2 KO mice produced significantly higher amount of IFN-α and IFN-β in response to PR8 virus infection than cells from WT mice. Mechanistically, ERK and IRF-3 activation was prolonged in MKP-2 KO cells infected with PR8 virus. The regulation of type I IFNs by MKP-2 was further investigated. Together, these data support the model that MKP-2 plays an important role in the regulation of type-I IFNs production, thus altering the innate immune responses during pulmonary influenza infection.