Assessing the roles of NK cells and IL-10 on the Circadian Gating of IAV-Infection Outcomes

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ESPR433
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Abstract: :

Background

Circadian rhythms provide an anticipatory mechanism for all living organisms. Such rhythms are evident in various facets of physiology, including immunology. We have demonstrated a time-of-day specific protection against influenza A (IAV) infection, a hallmark of circadian regulation. Mice infected with IAV (PR8) at the onset of their active phase (dusk) had 3-fold higher mortality than littermates infected at the onset of the rest phase (dawn). While both groups had comparable viral titers, the lungs from the dusk group showed more inflammation but less NK cells. Indeed, this protection was abolished with antibody depletion of NK cells prior to the infection, indicating NK cells are mediators of the circadian regulation of IAV infection. NK cells can be early producers of the immunosuppressive cytokine IL-10, which was differentially expressed in the two groups. However, the role of IL-10 in the circadian gating of IAV is unknown. We hypothesized the circadian protection against IAV is mediated by the immunoregulatory activity of NK cells via the IL10 secretion. 

Objective

Our aim was to determine (1) if the loss of NK cells abrogates circadian protection by affecting inflammation and immune-regulation and not by direct antiviral effects (2) If the immune-regulatory function of NK cells is mediated by IL10.

Design/Methods

8-16-week-old C57bl/6J mice were infected with 35 PFU of PR8 at either dawn or dusk. Mice were either treated with Nk1.1Ab (or PBS) 1 day prior to IAV infection or injected with Il10R1 antibody 1- and 3-days post infection (d.p.i). Lung and bronchioalveolar lavage (BAL) were harvested at serial time points following IAV infection in both cohorts.

Results

In line with our previous findings of circadian protection from IAV, NK cell-intact mice in the dawn group had lower BAL counts and lung immunopathology on histology. However, upon NK cell depletion, the two groups had comparably poor histology. Interestingly, the BAL counts remained lower in the dawn group on day 1, but had risen to match the dusk group by 2 and 6 d.p.i., suggesting the initiation of immunoregulation by NK cells is occurs around 2 d.p.i.. We next investigated IL10 as the mediator of NK cell immunoregulatory function. By blocking IL10 signaling pathways early in the course of infection, we abrogated the circadian protection. Upon histological analysis, we found immunopathology reminiscent of NK depletion, suggesting a common pathway of injury. 

Conclusion and Significance

We conclude that NK cells and IL-10 both contribute to the circadian gating of IAV infection outcomes. Further, the timeline of effects supports the possibility of NK cells directing this circadian effect through the production of IL10. In future, we plan on studying the role of NK cell clock and identifying the exact source of IL10 in the circadian context.

Children's Hospital of Philadelphia
Children's Hospital Of Philadelphia
Children's Hospital of Philadelphia
University of Pennsylvania
Children's Hospital of Philadelphia

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