Abstract
The transcription factor NR4A1 has emerged as a pivotal regulator of the inflammatory response and immune homeostasis. Although contribution of NR4A1 in the innate immune response has been demonstrated, its role in host defense against viral infection remains to be investigated. In the present study, we show that administration of cytosporone B (Csn-B), a specific agonist of NR4A1, to mice infected with influenza virus (IAV) reduces lung viral loads and improves pulmonary function. Our results demonstrate that administration of Csn-B to naive mice leads to a modest production of type 1 IFN. However, in IAV-infected mice, such production of IFNs is markedly increased following treatment with Csn-B. Our study also reveals that alveolar macrophages (AMs) appear to have a significant role in Csn-B effects, since selective depletion of AMs with clodronate liposome correlates with a marked reduction of IFN production, viral clearance and morbidity in IAV-infected mice. Furthermore, when reemergence of AMs is observed following clodronate liposome administration, an increased production of IFNs was detected in bronchoalveolar fluids of IAV-infected mice treated with Csn-B, supporting the contribution of AMs in Csn-B effects. While treatment of mice with Csn-B induces phosphorylation of transcriptional factors IRF3 and IRF7, the latter appears to be less indispensable since effects of Csn-B treatment on the synthesis of IFNs were slightly affected in IAV-infected mice lacking functional IRF7. Together, our results highlight the capacity of Csn-B and consequently of NR4A1 transcription factor in controlling IAV infection.
Highlights
The transcription factor NR4A1, named Nur77, has emerged as an important player of the immune response through its contribution to maintain homeostasis and its capacity to attenuate general inflammation [1, 2]
In order to determine whether cytosporone B (Csn-B) treatment can control influenza virus (IAV) infection, infected mice were treated daily with increasing doses of NR4A1 agonist post-infection and lung viral loads were assessed at day 5 post-infection, which corresponds to the highest replicative activity of IAV [26]
Results obtained indicate that Csn-B treatment improve these different parameters compared to untreated IAV-infected mice (Fig 2B, 2C, 2D and 2E)
Summary
The transcription factor NR4A1, named Nur, has emerged as an important player of the immune response through its contribution to maintain homeostasis and its capacity to attenuate general inflammation [1, 2]. NR4A1 was found to contribute to limit the influx of inflammatory monocytes and the production of inflammatory cytokines during myocardial infarction and NR4A1-dependent Ly6Clow monocytes have demonstrated a crucial role in mediating intravascular homeostasis by regulating necrosis of endothelial cells [4, 5]. These results are in line with the role of NR4A1 in the development of Ly6Clow patrolling monocytes which are recognized to be involved in the resolution of inflammation [6]. Overexpression of NR4A1 in transgenic mice attenuates the severity of inflammation in a collagen-induced arthritis model [7]
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