Acute viral infections trigger robust immune responses in the liver, which are characterized
by the activation of resident cell populations and the subsequent recruitment of additional
cells of innate and adaptive immunity. Here, the expression of inflammatory cytokines
by liver macrophages plays a central role. However, excessive inflammation and immunopathology
must be prevented. The intracellular MK2/3 kinase system is a key molecular mediator
as it controls cytokine expression mainly through tristetraprolin (TTP)-dependent
post-transcriptional regulation. However, it also controls a negative feedback loop
involving type I interferons (IFN-I) and IL-10. Thus, this kinase system is a linchpin
in the initiation and resolution of inflammatory mechanisms.
In this study, we infected macrophages in vitro or mice in vivo with the murine cytomegalovirus
(MCMV). Liver and serum were isolated for further analysis. MCMV is an accepted model
for human CMV infections, which lead to severe organ diseases and increased morbidity
or mortality especially in individuals with an immature or compromised immune system.
Therefore, investigating the immune responses induced by CMV is of high relevance.
Our data reveal that the deletion of the MK2/3 kinase system resulted in an abrogation
of two distinct MCMV-induced cytokine responses: 1) TTP-dependent inflammation including
TNF-α and IL-10, 2) TTP-independent antiviral IFN-I. Consequently, loss of IL-10-
and TNF-α-mediated signaling in macrophages improves the production of immune cell-activating
cytokines, such as IL-12 or CXCL9.
In conclusion, targeting the MK2/3-TTP interaction is a potential strategy to limit
inflammation while maintaining antiviral responses associated with CMV infections.
