C‐X‐C motif chemokine ligand 1 induced by Hedgehog signaling promotes mouse extrahepatic bile duct repair after acute injury

Abstract

Background and Aims: Inextrahepaticbileduct(EHBD)cholangiopathies, including primary sclerosing cholangitis, a reactive cholangiocyte phenotype is associated with inflammation and epithelial hyperproliferation. The signaling pathways involved in EHBD injury response are poorly understood.In this study, we investigated the role of Hedgehog (HH) signaling and its downstream effectors in controlling biliary proliferation and inflammation after EHBDinjury. Approach and Results: UsingmousebileductligationasanacuteEHBDinjury model, we used inhibitory paradigms to uncover mechanisms promoting the proliferative response. HH signaling was inhibited genetically in Gli1 −/− mice or by treating wild-type mice with LDE225. The role of neutrophils was tested using chemical (SB225002) and biological (lymphocyte antigen 6complexlocusG6D[Ly6G]antibodies)inhibitorsofneutrophilrecruitment. The cellular response was defined through morphometric quantification of proliferatingcellsandCD45+andLy6G+immunecellpopulations.Keysign-alingcomponentexpressionwasmeasuredandlocalizedtospecificEHBD cellular compartments by in situ hybridization, reporter strain analysis, and immunohistochemistry. Epithelial cell proliferation peaked 24 h after EHBD injury, preceded stromal cell proliferation, and was associated with neutrophil influx.IndianHHligandexpressioninthebiliaryepitheliumrapidlyincreased afterinjury.HH-respondingcellsandneutrophilchemoattractantC-X-Cmotif chemokine ligand 1 (CXCL1) expression mapped to EHBD stromal cells. Inhibition of HH signaling blocked CXCL1 induction, diminishing neutrophil

β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers

“… 43 , 44 Furthermore, blockade of Ly6G using a neutralizing antibody (clone 1A8) treatment has been found to decrease neutrophil tissue infiltration and impair their response to injury. 45 , 46 To assess the antitumor activity of β-Lap under conditions of neutrophil deficiency, we used an anti-Ly6G antibody to deplete neutrophils in C57BL/6 WT mice bearing subcutaneous MC38, TC-1 and EO771 tumors, as well as in BALB/c WT mice bearing 4T1 tumors. Mice were treated with a vehicle (20% HPβCD), β-Lap, anti-Ly6G antibody (clone 1A8), or a combination of β-Lap and anti-Ly6G antibody every other day for a total of four treatments, and tumor volume was measured to evaluate the antitumor activity.…”

TNF-α/IL-1β-licensed hADSCs alleviate cholestatic liver injury and fibrosis in mice via COX-2/PGE2 pathway

“…The consequent immune cascades initiated to promote the activation and recruitment of neutrophils ultimately led to an inflammatory response in the liver [ 48 – 50 ]. Studies have demonstrated that elevated levels of hepatocyte-specific proinflammatory cytokines, such as IL-1β [ 51 ], as well as enhanced expressions of CXCL1 [ 51 , 52 ] and CXCL2 [ 5 ], are possibly mediated by the Farnesoid X Receptor (Fxr)/early growth response 1 (Egr1) pathway [ 53 , 54 ]. Moreover, it has become clear that there is a complex mechanism of action among macrophages in regulating the fibrosis response.…”

Cholangiokines: undervalued modulators in the hepatic microenvironment

“…One fundamental feature of proliferating cholangiocytes is their enhanced secretion of variable pro-inflammatory cytokines, chemokines, growth factors, defensin, and other bioactive factors ( 99 ). With the timely repair of injury, inflammation would also resolve, and this scenario represents an acute inflammatory response without inducing aberrant hyperproliferation of cholangiocytes ( 131 ). However, if the damage persists to prevails over repair processes, cholangiocytes abnormally proliferate and induce chronic inflammation through interaction with various infiltrated immune cells, causing angiogenesis and fibrotic response in the liver, termed DR ( 14 ).…”

“…Reactive cholangiocytes regulate Th17 cell differentiation by IL-6 and IL-1β ( 167 ). In addition, fractalkine/CX3CL1 and CXCL1 are released by reactive cholangiocytes, which further recruit monocytes and T cells ( 109 , 131 , 168 , 169 ). In response to biliary injury, injured or senescent cholangiocytes dramatically release TNF-α and IL-6 ( 105 , 134 ).…”