Disrupting the intracellular MK2/3-TTP interaction reduces inflammation but preserves antiviral mechanisms in CMV infection

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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. Publication History Article published online: 20 January 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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