Keratin 23 is a stress-inducible marker of mouse and human ductular reaction in liver disease

doi:10.1016/j.jhep.2016.04.024

Journal of Hepatology

Volume 65, Issue 3, September 2016, Pages 552-559

https://doi.org/10.1016/j.jhep.2016.04.024 Get rights and content

Background & Aims

Keratins (K) constitute the epithelial intermediate filaments. Among them, K7/K19 are widely used markers of the regenerative liver response termed ductular reaction (DR) that consists of activated biliary epithelial cells (BECs) and hepatic progenitor cells (HPCs) and correlates with liver disease severity. In the present study we aimed to characterize K23 in the liver.

Methods

We analyzed the expression and localization of K23 in the digestive system under basal conditions as well as in various human and mouse liver diseases/stress models. Cell culture studies were used to study factors regulating K23 expression.

Results

In untreated mice, K23 was restricted to biliary epithelia. It was (together with K7/K19) markedly upregulated in three different DR/cholestatic injury models, i.e., multidrug resistance protein 2 (Mdr2) knockouts, animals treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine or subjected to bile duct ligation. K23 levels correlated with the DR marker Fn14 and immunofluorescence staining showed a distinct co-localization with K7/K19. In chronic human liver disease, K23 expression increased in patients with a more prominent inflammation/fibrosis. A dramatic upregulation (>200 times) was observed in patients with acute liver failure (ALF) and end-stage primary biliary cholangitis (PBC). Patients with alcoholic liver cirrhosis displayed increased K23 serum levels. In primary hepatocytes as well as hepatobiliary cell lines, treatment with TNF-related weak inducer of apoptosis (TWEAK), and the type I acute phase inducer interleukin (IL)-1β but not the type II inducer IL-6 elevated K23 expression.

Conclusions

K23 represents a specific, stress-inducible DR marker, whose levels correlate with liver disease severity. K23 may represent a useful non-invasive DR marker.

Lay summary

Ductular reaction represents a basic response to liver injury and correlates with liver disease severity. Our study identifies K23 as a novel ductular reaction marker in mice and humans.

Graphical abstract

Introduction

Keratins (K) are the intermediate filaments of epithelial cells and their appendages that are further subdivided into type I (including K9-K20) and type II (including K1-K8) proteins [1], [2]. Both types assemble in an equimolar ratio to form obligate heteropolymers that are expressed in a tissue-specific manner. Consequently, each cell type displays a characteristic type I-type II keratin repertoire [1], [2]. For example, K5/K14 and K1/K10 are produced in suprabasal and basal skin layers, respectively whereas K8/K18 constitute the major keratins of simple and glandular epithelia [1], [2]. K7/K19/K20/K23 are the secondary simple epithelial keratins that are less abundant and have a more restricted expression pattern [1], [2], [3].

The tissue-specific expression of keratins that remains stable during dedifferentiation makes keratins widely used diagnostic tools in both neoplastic and non-neoplastic diseases [3], [4], [5]. Due to their abundance and release into the blood during stress situations, keratin fragments constitute attractive non-invasive disease markers [5], [6]. Among them, antibodies M30 and M65 that recognize K18 epitopes, have attracted the most attention and are used to indicate the extent of hepatocellular damage and to predict disease outcome [5], [6], [7]. On the other hand, K7/K19 are absent from adult hepatocytes but are found in hepatic progenitor cells (HPCs), intermediate (i.e., not fully differentiated) hepatocytes and biliary epithelial cells (BECs) [7], [8]. Because of that, K7/K19 constitute one of the most widely used ductular reaction (DRs) markers.

DR represents a basic regenerative response of the liver to injury [9], [10]. It becomes even more important in patients with chronic liver diseases. In this situation, the normal liver regeneration that depends on division of mature hepatocytes becomes impaired [9], [10]. Compared to humans, DR is typically less prominent in murine liver injuries where it is seen primarily in cholestatic injury models. DR takes place at the interface of the portal and parenchymal compartment and consists of activated BECs and HPCs. Within DR, HPCs are bipotential and give rise to both BECs and (intermediate) hepatocytes [11]. Given that the extent of DR reflects the severity of underlying liver disease [9], [10], multiple studies showed that expression of K7/K19 increases with the severity of liver disease and represent a useful prognostic marker [12], [13], [14], [15], [16], [17]. This might be of particular importance in severe, fulminant liver disorders such as alcoholic hepatitis where increased K7 mRNA expression constituted an independent predictor of 90-day mortality [14]. Despite the obvious importance of DR, its extent can currently be evaluated only in situ since there are no established non-invasive DR markers. In that respect, CYFRA 21-1 assay detects K19 fragments in serum, however, its usefulness as a DR marker was not systematically analyzed [6].

To further explore the potential usefulness of keratins as diagnostic tools in liver disease, we analyzed the expression of K23 in the digestive system. K23 represents a largely unexplored, highly inducible keratin that was first detected in pancreatic cancer cell lines [18]. Since then, K23 was shown to be overexpressed in hepatocellular carcinoma and to constitute one of the most upregulated genes in steatohepatitis when compared to simple steatosis [19]. In our study, we demonstrate that K23 constitutes a specific DR marker that compared to both K7 and K19 is more restricted to the hepatobiliary system. K23 levels increase during the development of liver fibrosis and K23 expression becomes upregulated by the established DR inducer TNF-related weak inducer of apoptosis (TWEAK) or the type I acute phase inducer interleukin (IL)-1β. Moreover, K23 is found in the serum and is markedly elevated in patients with alcoholic liver cirrhosis when compared to liver-healthy subjects.

Section snippets

Human liver specimen

Following 57 previously characterized samples from patients who underwent a liver biopsy at the University of Ulm and at the Bondy Liver Unit between the years 2006–2010 were analyzed [16]: alcoholic liver disease (ALD) (15 cases), chronic hepatitis B (HBV, 9 cases), HCV (13 cases), NASH (12 cases), 8 control samples. Tissues were cut in half and used either for histological staining or frozen for RNA isolation/biochemical analysis (see below). We also studied liver explants from 7 subjects

K23 constitutes a novel marker of biliary epithelia and ductular reaction in mice

To further characterize the role of K23 in the digestive system, we first studied its expression in selected mouse tissues. K23 mRNA levels were higher in the gallbladder and CBD than the intestine and the liver. Among the other “ductal” keratins, K7 showed the highest expression in the gallbladder whereas K19 was found at similar levels in the intestinal tract and the gallbladder (Fig. 1A–C). A selective expression of K23 in the biliary system was confirmed on protein level (Fig. 1D) and via

Discussion

Our study demonstrates that in addition to K7/K19, K23 represents a specific marker of the biliary system and DR. Although the expression pattern of all three keratins is similar, some differences were observed. For example, K23, like K19 (but not K7), is expressed in the smaller branches of the biliary tree [26]. On the other hand, K23 is more broadly produced in injured periportal hepatocytes compared to K19 and in that sense resembles K7 [11], [12]. The induction of K23 in injured and

Financial support

This work was supported by the German Research Foundation grant STR 1095/4-1, SFB/TRR57 and the IZKF research group funding (to P.S. and C.T., C.L. and P.B.) and by the German Federal Ministry of Education and Research (BMBF 01GM1518A to PB). Dr. Zucman-Rossi is supported by Inserm and the Ligue Nationale Contre le Cancer.

Conflict of interest

The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Authors’ contributions

Study concept and design: NG, PS. Acquisition of data: NG, GKE, PL, GC, CP, PB. Analysis and interpretation of data: NG, GKE, PL, GC, CP, MZ, PB, PS. Drafting of the manuscript: NG, PS. Editing of the manuscript: all authors. Statistical analysis: NG, PS. Funding and study supervision: PS. Technical and material support: CL, HWZ, MZ, JZR, CT.

Acknowledgements

The expert technical assistance of Elke Preiß, Kristina Diepold, Linda Schaub and Ingrid Bauer is gratefully acknowledged. We thank Drs. Magin, Sandilands and Valentina M. Factor for her generous gifts of K23, K7 and A6 antibodies.

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Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients’ outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression.
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Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.
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As colonic inflammation, CRC and colonic metabolism (SCFA) exert changes on keratins, and keratins are involved in inflammatory, cancer and metabolic pathways, keratins are emerging as critical integrators of these complex pathways. The stress-responsive nature of keratins has been well-demonstrated in multiple organs including skin (Moll et al., 1982a, 1982b; Jin and Wang, 2014), liver (Nakamichi et al., 2005; Guldiken et al., 2015; Szabo et al., 2015; Guldiken et al., 2016), pancreas (Wögenstein et al., 2014; Zhong et al., 2004), kidney (Djudjaj et al., 2016) and lung (Sivaramakrishnan et al., 2009). In the human colon (see Section 3.2) and murine colon, stress-inducing factors such as inflammation, aging or microbiota affected the expression of keratins as well as their post-translational modifications (Helenius et al., 2016).
Keratin intermediate filament proteins are major cytoskeletal components of the mammalian simple layered columnar epithelium in the gastrointestinal tract. Human colon crypt epithelial cells express keratins 18, 19 and 20 as the major type I keratins, and keratin 8 as the type II keratin. Keratin expression patterns vary between species, and mouse colonocytes express keratin 7 as a second type II keratin. Colonic keratin patterns change during cell differentiation, such that K20 increases in the more differentiated crypt cells closer to the central lumen. Keratins provide a structural and mechanical scaffold to support cellular stability, integrity and stress protection in this rapidly regenerating tissue. They participate in central colonocyte processes including barrier function, ion transport, differentiation, proliferation and inflammatory signaling. The cell-specific keratin compositions in different epithelial tissues has allowed for the utilization of keratin-based diagnostic methods. Since the keratin expression pattern in tumors often resembles that in the primary tissue, it can be used to recognize metastases of colonic origin. This review focuses on recent findings on the biological functions of mammalian colon epithelial keratins obtained from pivotal in vivo models. We also discuss the diagnostic value of keratins in chronic colonic disease and known keratin alterations in colon pathologies. This review describes the biochemical properties of keratins and their molecular actions in colonic epithelial cells and highlights diagnostic data in colorectal cancer and inflammatory bowel disease patients, which may facilitate the recognition of disease subtypes and the establishment of personal therapies in the future.
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Both markers were increased in the Mdr2−/− mice compared with WT or Tr−/− and were even further increased in male Tr−/−Mdr2−/− mice (Figure 5) and at 45 days in female Tr−/−Mdr2−/− mice (Figure 5). Gene expression of Krt23, a stress-inducible marker of DR cells,18 was also more abundant in the Mdr2−/− and Tr−/−Mdr2−/− male and female mice (Figure 6). Tumor necrosis factor–related weak inducer of apoptosis (TWEAK), also known as TNF superfamily member 12 (Tnfsf12), is recognized as a primary driver of ductular reaction in mice.5
The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL; TNFSF10) receptor (TR) is a pro-apoptotic receptor whose contribution to chronic cholestatic liver disease is unclear. Herein, we examined TRAIL receptor signaling in a mouse model of cholestatic liver injury. TRAIL receptor-deficient (Tnsf10 or Tr^−/−) mice were crossbred with ATP binding cassette subfamily B member 4–deficient (Abcb4^−/−, alias Mdr2^−/−) mice. Male and female wild-type, Tr^−/−, Mdr2^−/−, and Tr^−/−Mdr2^−/− mice were assessed for liver injury, fibrosis, and ductular reactive (DR) cells. Macrophage subsets were examined by high-dimensional mass cytometry (time-of-flight mass cytometry). Mdr2^−/− and Tr^−/−Mdr2^−/− mice had elevated liver weights and serum alanine transferase values. However, fibrosis was primarily periductular in Mdr2^−/− mice, compared with extensive bridging fibrosis in Tr^−/−Mdr2^−/− mice. DR cell population was greatly expanded in the Tr^−/−Mdr2^−/− versus Mdr2^−/− mice. The expanded DR cell population in Tr^−/−Mdr2^−/− mice was due to decreased cell loss by apoptosis and not enhanced proliferation. As assessed by time-of-flight mass cytometry, total macrophages were more abundant in Tr^−/−Mdr2^−/− versus Mdr2^−/− mice, suggesting the DR cell population promotes macrophage-associated hepatic inflammation. Inhibition of monocyte-derived recruited macrophages using the CCR2/CCR5 antagonist cenicriviroc in the Mdr2^−/− mice resulted in further expansion of the DR cell population. In conclusion, genetic deletion of TRAIL receptor increased the DR cell population, macrophage accumulation, and hepatic fibrosis in the Mdr2^−/− model of cholestasis.
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A prominent group of genes that becomes upregulated in response to a cholestatic insult encodes keratins.2–4 In the liver, both hepatocytes and BECs express keratins (K) 8 and 18, whereas only BECs additionally contain K7, K19 and K23.4,5 Mutations in keratin genes resulting in unstable and abnormally organized keratin filaments (KFs) predispose their carriers to various liver diseases, including cholangiopathies.6,7
Plectin, a highly versatile cytolinker protein, controls intermediate filament cytoarchitecture and cellular stress response. In the present study, we investigate the role of plectin in the liver under basal conditions and in experimental cholestasis.
We generated liver-specific plectin knockout (Ple^Δalb) mice and analyzed them using two cholestatic liver injury models: bile duct ligation (BDL) and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding. Primary hepatocytes and a cholangiocyte cell line were used to address the impact of plectin on keratin filament organization and stability in vitro.
Plectin deficiency in hepatocytes and biliary epithelial cells led to aberrant keratin filament network organization, biliary tree malformations, and collapse of bile ducts and ductules. Further, plectin ablation significantly aggravated biliary damage upon cholestatic challenge. Coincidently, we observed a significant expansion of A6-positive progenitor cells in Ple^Δalb livers. After BDL, plectin-deficient bile ducts were prominently dilated with more frequent ruptures corresponding to an increased number of bile infarcts. In addition, more abundant keratin aggregates indicated less stable keratin filaments in Ple^Δalb hepatocytes. A transmission electron microscopy analysis revealed a compromised tight junction formation in plectin-deficient biliary epithelial cells. In addition, protein profiling showed increased expression of the adherens junction protein E-Cadherin, and inefficient upregulation of the desmosomal protein desmoplakin in response to BDL. In vitro analyses revealed a higher susceptibility of plectin-deficient keratin networks to stress-induced collapse, paralleled by elevated activation of p38 MAP kinase.
Our study shows that by maintaining proper keratin network cytoarchitecture and biliary epithelial stability, plectin plays a critical role in protecting the liver from stress elicited by cholestasis.
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Research ArticleKeratin 23 is a stress-inducible marker of mouse and human ductular reaction in liver disease☆

Background & Aims

Methods

Results

Conclusions

Lay summary

Graphical abstract

Introduction

Section snippets

Human liver specimen

K23 constitutes a novel marker of biliary epithelia and ductular reaction in mice

Discussion

Financial support

Conflict of interest

Authors’ contributions

Acknowledgements

Curr Opin Cell Biol

Curr Opin Cell Biol

Gastroenterology

J Hepatol

Trends Cell Biol

J Biol Chem

Oral Oncol

Keratins and disease at a glance

J Cell Sci

“IF-pathies”: a broad spectrum of intermediate filament-associated diseases

J Clin Invest

The human keratins: biology and pathology

Histochem Cell Biol

Keratins: Biomarkers and modulators of apoptotic and necrotic cell death in the liver

Hepatology

Keratins: markers and modulators of liver disease

Curr Opin Gastroenterol

Toward unraveling the complexity of simple epithelial keratins in human disease

J Clin Invest

Ductular reactions in human liver: diversity at the interface

Hepatology

Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered

Virchows Arch

Intermediate hepatobiliary cells predict an increased risk of hepatocarcinogenesis in patients with hepatitis C virus-related cirrhosis

Gastroenterology

Histologic predictors of fibrosis progression in liver allografts in patients with hepatitis C virus infection

Clin Gastroenterol Hepatol

Research Article
Keratin 23 is a stress-inducible marker of mouse and human ductular reaction in liver disease☆