1. Tpl2 Ablation Leads to Hypercytokinemia and Excessive Cellular Infiltration to the Lungs During Late Stages of Influenza Infection.
- Author
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Latha K, Jamison KF, and Watford WT
- Subjects
- Animals, Biomarkers blood, Cytokine Release Syndrome genetics, Cytokine Release Syndrome immunology, Cytokine Release Syndrome virology, Cytokines genetics, Disease Models, Animal, Female, Host-Pathogen Interactions, Influenza A Virus, H3N2 Subtype immunology, Lung immunology, Lung virology, MAP Kinase Kinase Kinases genetics, Male, Mice, Inbred C57BL, Mice, Knockout, Monocytes immunology, Monocytes virology, Neutrophil Infiltration, Neutrophils immunology, Neutrophils virology, Nitric Oxide Synthase Type II genetics, Nitric Oxide Synthase Type II metabolism, Orthomyxoviridae Infections genetics, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections virology, Proto-Oncogene Proteins genetics, Suppressor of Cytokine Signaling 1 Protein genetics, Suppressor of Cytokine Signaling 1 Protein metabolism, Time Factors, Mice, Cytokine Release Syndrome metabolism, Cytokines blood, Influenza A Virus, H3N2 Subtype pathogenicity, Lung metabolism, MAP Kinase Kinase Kinases deficiency, Monocytes metabolism, Neutrophils metabolism, Orthomyxoviridae Infections metabolism, Proto-Oncogene Proteins deficiency
- Abstract
Tumor progression locus 2 (Tpl2) is a serine-threonine kinase known to promote inflammation in response to various pathogen-associated molecular patterns (PAMPs), inflammatory cytokines and G-protein-coupled receptors and consequently aids in host resistance to pathogens. We have recently shown that Tpl2
-/- mice succumb to infection with a low-pathogenicity strain of influenza (x31, H3N2) by an unknown mechanism. In this study, we sought to characterize the cytokine and immune cell profile of influenza-infected Tpl2-/- mice to gain insight into its host protective effects. Although Tpl2-/- mice display modestly impaired viral control, no virus was observed in the lungs of Tpl2-/- mice on the day of peak morbidity and mortality suggesting that morbidity is not due to virus cytopathic effects but rather to an overactive antiviral immune response. Indeed, increased levels of interferon-β (IFN-β), the IFN-inducible monocyte chemoattractant protein-1 (MCP-1, CCL2), Macrophage inflammatory protein 1 alpha (MIP-1α; CCL3), MIP-1β (CCL4), RANTES (CCL5), IP-10 (CXCL10) and Interferon-γ (IFN-γ) was observed in the lungs of influenza-infected Tpl2-/- mice at 7 days post infection (dpi). Elevated cytokine and chemokines were accompanied by increased infiltration of the lungs with inflammatory monocytes and neutrophils. Additionally, we noted that increased IFN-β correlated with increased CCL2, CXCL1 and nitric oxide synthase (NOS2) expression in the lungs, which has been associated with severe influenza infections. Bone marrow chimeras with Tpl2 ablation localized to radioresistant cells confirmed that Tpl2 functions, at least in part, within radioresistant cells to limit pro-inflammatory response to viral infection. Collectively, this study suggests that Tpl2 tempers inflammation during influenza infection by constraining the production of interferons and chemokines which are known to promote the recruitment of detrimental inflammatory monocytes and neutrophils., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Latha, Jamison and Watford.)- Published
- 2021
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