tetano
Editor, Senior Moderator
Inflammation
. 2022 Oct 13;1-20.
doi: 10.1007/s10753-022-01736-8. Online ahead of print.
The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling
Krishna Latha[SUP] 1 [/SUP], Yesha Patel[SUP] 2 [/SUP], Sanjana Rao[SUP] 3 [/SUP], Wendy T Watford[SUP] 4 [/SUP]
Affiliations
Abstract
The most prominent host response to viral infection is the production of type 1 interferons (T1 IFNs). One host regulator of the T1 IFNs is the serine-threonine kinase, tumor progression locus 2 (TPL2). We have previously demonstrated that Tpl2[SUP]-/-[/SUP] mice succumb to infection with a low-pathogenicity influenza A strain (x31), in association with with increased pulmonary levels of interferon-β (IFN-β), chemokine CCL2, and excessive monocyte and neutrophil pulmonary infiltration. TPL2-dependent overexpression of IFN-β has been implicated in enhanced susceptibility to Mycobacterium tuberculosis; therefore, we examined the role of T1 IFNs in susceptibility of Tpl2[SUP]-/-[/SUP] mice to influenza. CCL2 overexpression and monocyte recruitment were normalized in Ifnar1[SUP]-/-[/SUP]Tpl2[SUP]-/-[/SUP] mice, confirming that TPL2 constrains inflammatory monocyte recruitment via inhibition of the T1 IFN/CCL2 axis. Unexpectedly, excessive neutrophil recruitment in Ifnar1[SUP]-/-[/SUP] strains was further exacerbated by simultaneous TPL2 genetic ablation in Ifnar1[SUP]-/-[/SUP]Tpl2[SUP]-/-[/SUP] by 7 dpi, accompanied by overexpression of neutrophil-regulating cytokines, CXCL1 and IFN-λ. Collectively, our data suggest that TPL2 and T1 IFNs synergize to inhibit neutrophil recruitment. However, treatment with the neutrophil-depleting anti-Ly6G antibody showed only a modest improvement in disease. Analysis of sorted innate immune populations revealed redundant expression of inflammatory mediators among neutrophils, inflammatory monocytes and alveolar macrophages. These findings suggest that targeting a single cell type or mediator may be inadequate to control severe disease characterized by a mixed inflammatory exudate. Future studies will consider TPL2-regulated pathways as potential predictors of severe influenza progression as well as investigate novel methods to modulate TPL2 function during viral infection.
Keywords: Influenza; Interferons; Neutrophils; TPL2.
. 2022 Oct 13;1-20.
doi: 10.1007/s10753-022-01736-8. Online ahead of print.
The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling
Krishna Latha[SUP] 1 [/SUP], Yesha Patel[SUP] 2 [/SUP], Sanjana Rao[SUP] 3 [/SUP], Wendy T Watford[SUP] 4 [/SUP]
Affiliations
- PMID: 36227523
- PMCID: PMC9558022
- DOI: 10.1007/s10753-022-01736-8
Abstract
The most prominent host response to viral infection is the production of type 1 interferons (T1 IFNs). One host regulator of the T1 IFNs is the serine-threonine kinase, tumor progression locus 2 (TPL2). We have previously demonstrated that Tpl2[SUP]-/-[/SUP] mice succumb to infection with a low-pathogenicity influenza A strain (x31), in association with with increased pulmonary levels of interferon-β (IFN-β), chemokine CCL2, and excessive monocyte and neutrophil pulmonary infiltration. TPL2-dependent overexpression of IFN-β has been implicated in enhanced susceptibility to Mycobacterium tuberculosis; therefore, we examined the role of T1 IFNs in susceptibility of Tpl2[SUP]-/-[/SUP] mice to influenza. CCL2 overexpression and monocyte recruitment were normalized in Ifnar1[SUP]-/-[/SUP]Tpl2[SUP]-/-[/SUP] mice, confirming that TPL2 constrains inflammatory monocyte recruitment via inhibition of the T1 IFN/CCL2 axis. Unexpectedly, excessive neutrophil recruitment in Ifnar1[SUP]-/-[/SUP] strains was further exacerbated by simultaneous TPL2 genetic ablation in Ifnar1[SUP]-/-[/SUP]Tpl2[SUP]-/-[/SUP] by 7 dpi, accompanied by overexpression of neutrophil-regulating cytokines, CXCL1 and IFN-λ. Collectively, our data suggest that TPL2 and T1 IFNs synergize to inhibit neutrophil recruitment. However, treatment with the neutrophil-depleting anti-Ly6G antibody showed only a modest improvement in disease. Analysis of sorted innate immune populations revealed redundant expression of inflammatory mediators among neutrophils, inflammatory monocytes and alveolar macrophages. These findings suggest that targeting a single cell type or mediator may be inadequate to control severe disease characterized by a mixed inflammatory exudate. Future studies will consider TPL2-regulated pathways as potential predictors of severe influenza progression as well as investigate novel methods to modulate TPL2 function during viral infection.
Keywords: Influenza; Interferons; Neutrophils; TPL2.