| First Author | Latha K | Year | 2023 |
| Journal | Inflammation | Volume | 46 |
| Issue | 1 | Pages | 322-341 |
| PubMed ID | 36227523 | Mgi Jnum | J:351376 |
| Mgi Id | MGI:7663154 | Doi | 10.1007/s10753-022-01736-8 |
| Citation | Latha K, et al. (2023) The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling. Inflammation 46(1):322-341 |
| abstractText | 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(-/-) mice succumb to infection with a low-pathogenicity influenza A strain (x31), in association with with increased pulmonary levels of interferon-beta (IFN-beta), chemokine CCL2, and excessive monocyte and neutrophil pulmonary infiltration. TPL2-dependent overexpression of IFN-beta has been implicated in enhanced susceptibility to Mycobacterium tuberculosis; therefore, we examined the role of T1 IFNs in susceptibility of Tpl2(-/-) mice to influenza. CCL2 overexpression and monocyte recruitment were normalized in Ifnar1(-/-)Tpl2(-/-) mice, confirming that TPL2 constrains inflammatory monocyte recruitment via inhibition of the T1 IFN/CCL2 axis. Unexpectedly, excessive neutrophil recruitment in Ifnar1(-/-) strains was further exacerbated by simultaneous TPL2 genetic ablation in Ifnar1(-/-)Tpl2(-/-) by 7 dpi, accompanied by overexpression of neutrophil-regulating cytokines, CXCL1 and IFN-lambda. 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. |
