REV-ERB negatively regulates NLRP6 transcription and reduces the severity of Salmonella infection in mice

Non-typhoidal Salmonella infection is among the most frequent foodborne diseases threatening human health worldwide. The host circadian clock orchestrates daily rhythms to adapt to environmental changes, including coordinating immune function in response to potential infections. However, the molecular mechanisms underlying the interplay between the circadian clock and the immune system in modulating infection processes are incompletely understood. Here, we demonstrate that NLRP6, a novel nucleotide-oligomerization domain (NOD)-like receptor (NLR) family member highly expressed in the intestine, is closely associated with the differential day-night response to Salmonella infection. The core clock component REV-ERB alpha negatively regulates NLRP6 transcription, leading to the rhythmic expression of NLRP6 and the secretion of IL -18 in intestinal epithelial cells, playing a crucial role in mediating the differential day-night response to Salmonella infection. Activating REV-ERB alpha with agonist SR9009 in wild -type mice attenuated the severity of infection by decreasing the NLRP6 level in intestinal epithelial cells. Our findings provide new insights into the association between the host circadian clock and the immune response to enteric infections by revealing the regulation of Salmonella infection via the inhibitory effect of REV-ERB alpha on NLRP6 transcription. Targeting REV-ERB alpha to modulate NLRP6 activation may be a potential therapeutic strategy for bacterial infections.