| First Author | Cox SL | Year | 2023 |
| Journal | FASEB J | Volume | 37 |
| Issue | 2 | Pages | e22753 |
| PubMed ID | 36624683 | Mgi Jnum | J:338759 |
| Mgi Id | MGI:7514432 | Doi | 10.1096/fj.202201456R |
| Citation | Cox SL, et al. (2023) Circadian disruption in lung fibroblasts enhances NF-kappaB activity to exacerbate neutrophil recruitment. FASEB J 37(2):e22753 |
| abstractText | Fibroblasts are stromal cells abundant throughout tissues, including the lungs. Fibroblasts are integral coordinators of immune cell recruitment through chemokine secretion. Circadian rhythms direct the recruitment of immune cells to the lung, which in turn impacts response to infection and survival. Although fibroblasts display robust circadian rhythms, the contribution of the fibroblast molecular clock to lung-specific migration of immune cells and recruitment remains to be established. Mice challenged intranasally with lipopolysaccharide (LPS) at dusk showed increased expression of the pro-inflammatory cytokine IL-1beta and chemokine CXCL5 in the lung, which was accompanied by increased neutrophil recruitment. Primary lung fibroblasts with knockdown of the core clock gene Bmal1 and immortalized Bmal1(-/-) lung fibroblasts also displayed increased Cxcl5 expression under IL-1beta stimulation. Conditioned media obtained from IL-1beta-stimulated Bmal1(-/-) immortalized fibroblasts-induced greater neutrophil migration compared with Bmal1(+/+) lung fibroblast controls. Phosphorylation of the NF-kappaB subunit, p65, was enhanced in IL-1beta-stimulated Bmal1(-/-) lung fibroblasts, and pharmacological inhibition of NF-kappaB attenuated the enhanced CXCL5 production and neutrophil recruitment observed in these cells. Collectively, these results demonstrate that Bmal1 represses NF-kappaB activity in lung fibroblasts to control chemokine expression and immune cell recruitment during an inflammatory response. |
