Bile acid-sensitive tuft cells regulate biliary neutrophil influx.
Claire E O'LearyJulia Sbierski-KindMaya E KotasJohanna C WagnerHong-Erh LiangAndrew W SchroederJeshua C de TenorioJakob von MoltkeRoberto R Ricardo-GonzalezWalter L EckalbarAri B MolofskyChristoph SchneiderRichard M LocksleyPublished in: Science immunology (2022)
Inflammation and dysfunction of the extrahepatic biliary tree are common causes of human pathology, including gallstones and cholangiocarcinoma. Despite this, we know little about the local regulation of biliary inflammation. Tuft cells, rare sensory epithelial cells, are particularly prevalent in the mucosa of the gallbladder and extrahepatic bile ducts. Here, we show that biliary tuft cells express a core genetic tuft cell program in addition to a tissue-specific gene signature and, in contrast to small intestinal tuft cells, decreased postnatally, coincident with maturation of bile acid production. Manipulation of enterohepatic bile acid recirculation revealed that tuft cell abundance is negatively regulated by bile acids, including in a model of obstructive cholestasis in which inflammatory infiltration of the biliary tree correlated with loss of tuft cells. Unexpectedly, tuft cell-deficient mice spontaneously displayed an increased gallbladder epithelial inflammatory gene signature accompanied by neutrophil infiltration that was modulated by the microbiome. We propose that biliary tuft cells function as bile acid-sensitive negative regulators of inflammation in biliary tissues and serve to limit inflammation under homeostatic conditions.
Keyphrases
- induced apoptosis
- oxidative stress
- cell cycle arrest
- single cell
- endothelial cells
- endoplasmic reticulum stress
- magnetic resonance imaging
- genome wide
- gene expression
- dna methylation
- signaling pathway
- cell death
- copy number
- transcription factor
- pi k akt
- quality improvement
- microbial community
- bone marrow
- induced pluripotent stem cells
- antibiotic resistance genes