Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications

Weiskirchen, Ralf; Weiskirchen, Sabine; Tacke, Frank

doi:10.1016/j.mam.2018.06.003

Cited by 415 publications

(339 citation statements)

References 179 publications

Supporting

Mentioning

337

Contrasting

Unclassified

Order By: Relevance

“…Sterile inflammation and regeneration are two biological processes that are tightly related to wound healing, but if uncontrolled could lead to scarring and fibrotic responses, contributing to the long term to organ loss of function . Among cells involved in the modulation of these crucial functions, several types of macrophages play a central role in the clearance of dying/dead cells, and promote tissue repair by secreting a broad variety of molecules, such as cytokines, chemokines, or alarmins, that either maintain the inflammation process and/or activate tissue myofibroblasts in charge of synthesizing extracellular matrix components to promote tissue architecture restoration .…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Among cells involved in the modulation of these crucial functions, several types of macrophages play a central role in the clearance of dying/dead cells, and promote tissue repair by secreting a broad variety of molecules, such as cytokines, chemokines, or alarmins, [1][2][3][4] that either maintain the inflammation process and/or activate tissue myofibroblasts in charge of synthesizing extracellular matrix components to promote tissue architecture restoration. 2,5 Globally in the context of wound healing, immunostimulatory molecules originating either from macrophages (alarmins) or dying cells (such as damage-associated molecular patterns [DAMPs]) have been characterized as both pro-inflammatory but also as pro-regenerating agents involved in progenitor cell proliferation and differentiation, 1,3,4 thus potentially involve during chronic tissue injury, in inflammation and fibrosis processes which are now supported by several reports in the heart and lungs. 6,7 Among pro-inflammatory and pro-repair agents secreted by macrophages, high mobility group box 1 (HMGB1), also known for its alarmin and DAMP properties, has drawn a lot of attention as it is considered as an attractive target to treat acute and chronic inflammatory diseases [8][9][10] and is also envisioned as a relevant biomarker of tissue injury 11,12 in humans.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

et al. 2019

View full text Add to dashboard Cite

Alarmins and damage‐associated molecular patterns (DAMPs) are powerful inflammatory mediators, capable of initiating and maintaining sterile inflammation during acute or chronic tissue injury. Recent evidence suggests that alarmins/DAMPs may also trigger tissue regeneration and repair, suggesting a potential contribution to tissue fibrogenesis. High mobility group B1 (HMGB1), a bona fide alarmin/DAMP, may be released passively by necrotic cells or actively secreted by innate immune cells. Macrophages can release large amounts of HMGB1 and play a key role in wound healing and regeneration processes. Here, we hypothesized that macrophages may be a key source of HMGB1 and thereby contribute to wound healing and fibrogenesis. Surprisingly, cell‐specific deletion approaches, demonstrated that macrophage‐derived HMGB1 is not involved in tissue fibrogenesis in multiple organs with different underlying pathologies. Compared to control HMGB1Flox mice, mice with macrophage‐specific HMGB1 deletion (HMGB1ΔMac) do not display any modification of fibrogenesis in the liver after CCL4 or thioacetamide treatment and bile duct ligation; in the kidney following unilateral ureter obstruction; and in the heart after transverse aortic constriction. Of note, even under thermoneutral housing, known to exacerbate inflammation and fibrosis features, HMGB1ΔMac mice do not show impairment of fibrogenesis. In conclusion, our study clearly establishes that macrophage‐derived HMGB1 does not contribute to tissue repair and fibrogenesis.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

et al. 2019

View full text Add to dashboard Cite

show abstract

“…We believe that our study will shed light on a novel physiological function of PROM1 in liver fibrosis. In addition to the liver, fibrosis progresses in other organs such as the heart, lung, kidney, and skin where PROM1 is highly expressed 17, 32, 33 . Because the role of SMAD7 during fibrosis progression has been extensively studied in these organs 34–37 , a PROM1-SMAD7 axis will provide a better insight into understanding fibrosis in other organs.…”

Section: Discussionmentioning

confidence: 99%

Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

Lee¹,

Dong²,

Um³

et al. 2019

Preprint

View full text Add to dashboard Cite

Background and Aims:Prominin-1 (PROM1) is known to be upregulated in hepatocytic progenitor cells (HPCs) and cholangiocytes of fibrotic livers. To understand the function of upregulated PROM1 during liver fibrosis, we analyzed liver fibrosis from global and liverspecific Prom1 knockout mice and investigated the molecular mechanism of how Prom1 protects the liver against liver fibrosis. Methods:We analyzed PROM1 expression from human liver with mild and severe liver fibrosis (n=4-9). Liver fibrosis was induced by carbon tetrachloride (CCl 4 ) treatment and bile duct ligation (BDL) from wild type and global and liver-specific knockout mice (n=3-13).The severity of liver fibrosis was determined by qRT-PCR, immunostaining and immunoblotting for fibrotic markers such as αSMA, collagen. TGFβ signaling was also analyzed from fibrotic liver and primary hepatocytes of wild type and global and liverspecific knockout mice (n=3-5). Molecular interaction between PROM1 and SMAD7 was determined by endogenous and exogenous co-immunoprecipitation.Results: PROM1 was found in the plasma membranes of both healthy and fibrotic hepatocytes and cholangiocytes. Global Prom1 knockout aggravated BDL-and CCl 4 -induced liver fibrosis. Prom1 -/hepatocytes showed increased TGFβ signaling due to reduced SMAD7 protein expression compared to that in wild-type hepatocytes. PROM1 prevented SMURF2-induced SMAD7 ubiquitination and degradation by interfering with the molecular association of SMAD7 with SMURF2. We also demonstrated that liver-specific Prom 1 knockout aggravated BDL-induced liver fibrosis due to reduced levels of SMAD7. Conclusion:Hepatocytic PROM1 stabilizes SMAD7, preventing TGFβ signaling. Thus, PROM1 is necessary for the negative regulation of TGFβ signaling during liver fibrosis.

show abstract

“…The chemokines and proinflammatory cytokines stimulate immune cell infiltration and activation, respectively. Activated immune cells subsequently release profibrogenic factors promoting mesenchymal cell trans‐differentiation . Other nonpeptidic fibrogenic mediators including reactive oxygen species (ROS), lipid mediators (e.g., exosomes from stressed hepatocytes), and acetaldehyde have been identified recently .…”

Section: Advanced Liver Diseasesmentioning

confidence: 99%

“…Activated immune cells subsequently release profibrogenic factors promoting mesenchymal cell trans‐differentiation . Other nonpeptidic fibrogenic mediators including reactive oxygen species (ROS), lipid mediators (e.g., exosomes from stressed hepatocytes), and acetaldehyde have been identified recently . For instance, ROS promotes hepatocyte damage by disrupting integrity of lipids, proteins, and DNA, which stimulates the production of fibrogenic mediators by KCs.…”

Section: Advanced Liver Diseasesmentioning

confidence: 99%

Nanomaterial Manipulation of Immune Microenvironment in the Diseased Liver

Huang

2018

Adv Funct Materials

View full text Add to dashboard Cite

The liver contains intricate immunological mechanisms, capable of inducing both immune activation and suppression for the maintenance of a homeostatic immune environment. From an immunological point of view, chronic liver disease is indeed a result of the imbalance of pro-and anti-inflammatory responses. Therefore, application of immunotherapy in liver diseases is logical and contains a huge potential for future development. Despite rapid advances in immunotherapy, research at the interdisciplinary interface of immunology and material science is important for further enhancement of immunotherapeutic efficiency and reduction of side effects. Moreover, the liver is particularly suitable for the application of nanomaterial-based immunotherapy due to its biological filtration function to sequester a majority of administrated nanoparticles from systemic circulation. Here, an insight of advanced liver diseases and how liver cells exert their immune functions in the diseased liver is summarized first to provide basic principles for therapeutic application, followed by an overview of the latest studies on nanomaterial-based immunotherapy for liver diseases.

show abstract

Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications

Cited by 415 publications

References 179 publications

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

Macrophage‐derived HMGB1 is dispensable for tissue fibrogenesis

Hepatocytic Prominin-1 protects against liver fibrosis by stabilizing the SMAD7 protein

Nanomaterial Manipulation of Immune Microenvironment in the Diseased Liver

Contact Info

Product

Resources

About