Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) deletion in myeloid cells augments cholestatic liver injury
Ductular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. Herein, we posit that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanates from recruited macrophages and restrains DR cell expansion, thereby limiting cholestatic liver injury. Wild type (WT), Trail f...
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Veröffentlicht in: | Scientific reports 2024-01, Vol.14 (1), p.2145-14, Article 2145 |
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Zusammenfassung: | Ductular reactive (DR) cells exacerbate cholestatic liver injury and fibrosis. Herein, we posit that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emanates from recruited macrophages and restrains DR cell expansion, thereby limiting cholestatic liver injury. Wild type (WT),
Trail
fl/fl
and myeloid-specific
Trail
deleted (
Trail
Δmye
) C57BL/6 mice were exposed to DDC diet-induced cholestatic liver injury, which induced hepatomegaly and liver injury as compared to control diet-fed mice. However, parameters of liver injury, fibrosis, and inflammation were all increased in the
Trail
Δmye
mice as compared to the WT and
Trail
fl/fl
mice. High dimensional mass cytometry indicated that cholestasis resulted in increased hepatic recruitment of subsets of macrophages and neutrophils in the
Trail
Δmye
mice. Spatial transcriptomics analysis revealed that the PanCK
+
cholangiocytes from
Trail
Δmye
mice had increased expression of the known myeloid attractants
S100a8, Cxcl5, Cx3cl1,
and
Cxcl1.
Additionally, in situ hybridization of
Cxcl1,
a potent neutrophil chemoattractant, demonstrated an increased expression in CK19
+
cholangiocytes of
Trail
Δmye
mice. Collectively, these data suggest that TRAIL from myeloid cells, particularly macrophages, restrains a subset of DR cells (i.e.,
Cxcl1
positive cells), limiting liver inflammation and fibrosis. Reprogramming macrophages to express TRAIL may be salutary in cholestasis. |
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ISSN: | 2045-2322 2045-2322 |
DOI: | 10.1038/s41598-024-52710-3 |