Role of NK cells in circadian regulation of lung inflammation

Abstract

Abstract Circadian rhythms form an anticipatory system wherein various aspects of cellular physiology oscillate across a 24hrs period; these rhythms have been known to modulate various facets of immunity. We have previously shown that mice infected with Influenza A virus (IAV) at dusk had 3-fold higher mortality than littermates infected at dawn--a hallmark of circadian regulation. This time-of-day specific protection was lost when NK cells were depleted just before the infection, suggesting a role of NK cells in mediating the circadian regulation of IAV infection. We investigated the mechanism underlying the role of NK cells, both cell-intrinsic or extrinsic in circadian regulation of lung injury. We noted that viral clearance was unaffected, but immunopathology was markedly worse in the NK depleted mice than the controls. Next, we investigated the effect of the loss of the circadian clock on NK cell behavior and found that splenic and pulmonary NK cells in naïve mice with a disrupted circadian clock have a less mature phenotype than control NK cells with intact clock. Our transcriptomic profiling of NK cells sorted from clock-intact versus clock-disrupted animals revealed that several genes that regulate cell cycle progression and functional maturity of NK cells were differentially expressed across the two groups. Pulmonary NK cells from clock mutant mice were less mature than clock-intact mice. Finally, the Ncr1cre+Bmal1fl/flmice (core clock gene Bmal1deleted in NK cells) infected with IAV had higher mortality through heightened immunopathology but not delayed viral clearance. In summary, these data show that NK cell-autonomous clock boost host tolerance to mediate circadian protection from IAV infection. Supported by grants from NIH (R01HL155934-01A1, R01HL147472, R01AI137062-01)