Absence of kynurenine 3-monooxygenase reduces mortality of acute viral myocarditis in mice

•Kynurenine 3-monooxygenase (KMO) deficiency reduced mortality after EMCV infection.•KMO−/− mice markedly increased the levels of serum kynurenine and kynurenic acid.•The production of chemokines in KMO−/− mice was suppressed after EMCV infection.

Infection of the encephalomyocarditis virus (EMCV) in mice is an established model for viral myocarditis. Previously, we have demonstrated that indoleamine 2,3-dioxygenase (IDO), an L-tryptophan − kynurenine pathway (KP) enzyme, affects acute viral myocarditis. However, the roles of KP metabolites in EMCV infection remain unclear. Kynurenine 3-monooxygenase (KMO) is one of the key regulatory enzymes, which metabolizes kynurenine to 3-hydroxykynurenine in the KP. Therefore, we examined the role of KMO in acute viral infection by comparing between KMO−/− mice and KMO+/+ mice. KMO deficiency resulted in suppressed mortality after EMCV infection. The number of infiltrating cells and F4/80+ cells in KMO−/− mice was suppressed compared with those in KMO+/+ mice. KMO−/− mice showed significantly increased levels of serum KP metabolites, and induction of KMO expression upon EMCV infection was involved in its effect on mortality through EMCV suppression. Furthermore, KMO−/− mice showed significantly suppression of CCL2, CCL3 and CCL4 on day 2 and CXCL1 on day 4 after infection. These results suggest that increased KP metabolites reduced chemokine production, resulting in suppressed mortality upon KMO knockdown in EMCV infection. KP metabolites may thus provide an effective strategy for treating acute viral myocarditis.

Graphical abstractSchematic over view of the role of KMO regulation upon EMCV infection &z.rtrif; EMCV infection induced IDO activation and increased the KP metabolites. KMO deficiency increased KP metabolites (KYN, KA, and AA), and KYN decreased the chemokine expression via NF-κB signaling. The increased KP metabolites suppressed the immune cells. The KP metabolites might contribute to suppress infected cells and ameliorate the survival rate.Download high-res image (125KB)Download full-size image