Biglycan: A regulator of hepatorenal inflammation and autophagy
Introduction
Emerging evidence highlights the fundamental implications of the extracellular matrix (ECM) in the regulation of inflammation [1], [2], [3], [4] and autophagy [5], [6], [7]. Inflammation is a critical body response to microbial invasion or to tissue injury under aseptic conditions [1]. Uncontrolled pathways boosting inflammation (e.g. triggered by nuclear factor kappa–light-chain enhancer of activated B cells (NF-κB), inflammasome/caspase-1/interleukin (IL)-1β and type I interferon) are a major cause of organ damage and fibrosis [8], [9], [10], [11], [12], [13], [14]. Autophagy is a highly conserved cellular process in which cytoplasmatic material, protein aggregates or damaged organelles are sequestered into double-membrane vesicles and delivered for lysosomal degradation [15], [16], [17], [18]. Moreover, autophagy is considered a critical defense mechanism to excessive inflammation, regulating sterile and pathogen-induced inflammatory response, and immune cell maturation and viability [19], [20], [21], [22]. Pro-autophagic pathways have been shown to suppress inflammasome activity either by targeting ubiquitinated apoptosis-associated speck-like protein or directly targeting pro-inflammatory cytokine IL-1β for degradation [20,23,24]. Additionally, various autophagy-related genes (e.g. Atg5, Atg7, Atg16-like 1 protein) are implicated in the regulation of pro-inflammatory cytokines and generation of reactive oxygen species (ROS) [25].
Among various components of the ECM, proteoglycans, which are composed of a protein core and glycosaminoglycan side chains [26,27], are particularly predisposed to interact with numerous receptors and orchestrate their signaling [2]. Indeed, proteoglycans have been associated with various diseases [28], [29], [30], [31], [32], [33], and identified as regulators of inflammation by acting as damage-associated molecular patterns (DAMPs) [1].
Beyond their function as DAMPs [34,35], biglycan and decorin, two members of the class I small leucine rich proteoglycans (SLRPs) [27], were also identified as inducers of autophagy. While biglycan has been demonstrated to evoke autophagy in macrophages [36], decorin promotes autophagy induction in endothelial cells [[37], [38], [39]]. For further details regarding the role of decorin in inflammation and autophagy please refer to recent review publications [40], [41], [42], [43], [44].
It is well recognized that ECM-bound biglycan plays a critical role in ECM assembly and organization [45,46], and has a key role in skeletal tissues homeostasis [47]. An emerging body of evidence has led to a paradigm shift in biglycan function. While it was previously regarded as an inert ECM derivate, it is now clear that biglycan can be released from the ECM in response to tissue injury via partial proteolysis [35,38]. In its soluble form biglycan acts as a signaling molecule boosting NF-κB- and the inflammasome/caspase-1-pathways [1,35,49,50]. As endogenous ligand of innate immunity Toll-like receptor (TLR)-2 and TLR4 and trigger of the (NOD-, LRR- and pyrin domain-containing protein 3) NLRP3 inflammasome, soluble biglycan autonomously stimulates sterile inflammation [35,48,49,51,52]. In microbial inflammation, soluble biglycan potentiates the inflammatory response to Gram-positive and Gram-negative bacteria via a second TLR that is not involved in pathogen sensing [2,36,48,[52], [53], [54], [55]].
A rapid release of biglycan from the ECM storage, is followed by de novo biglycan production by activated macrophages and tissue resident cells [35]. ECM-derived and newly produced biglycan is creating a feed-forward cycle that triggers inflammation in an autocrine and paracrine manner. If biglycan production exceeds the organ capacity for proteoglycan sequestration, soluble biglycan is secreted into the circulation and transported with the blood to various organs [4,50]. Thus, it is conceivable that circulating biglycan can act as a messenger that promotes crosstalk between organs (e.g. hepatorenal dysfunction).
Novel findings have identified biglycan as a high-affinity ligand to TLR2/4 co-receptor CD14 [54,56,57] and to TLR4 co-receptor CD44 [36]. Interestingly, by interacting with TLR4 biglycan can mediate both pro-inflammatory and pro-autophagic downstream effects depending on the “choice” of the co-receptor CD14 and CD44, respectively [36,[54], [55], [56], [57]]. Thus, by promoting a switch between inflammation and autophagy, biglycan triggers either chronification of inflammation and organ damage, or resolution of the inflammatory response and tissue repair (Figure 1).
Hepatorenal dysfunction represents a classic example for inter-organ crosstalk, in which functional and molecular alterations of the cirrhotic liver can promote the development of renal failure. Acute kidney injury (AKI) constitutes one of the most common complications of liver cirrhosis and is associated with high morbidity and mortality but has limited treatment options [58], [59], [60]. In recent years, our understanding of traditional pathogenetic mechanisms of hepatorenal dysfunction in liver cirrhosis have severely broadened, mainly driven by implications of the systemic inflammation hypothesis [61]. In the past, hepatorenal dysfunction has been seen as functional consequence of a portal hypertension with shear-stress induced endothelial dysfunction, consecutive splanchnic arterial vasodilation, and reduced effective renal arterial blood flow [62], [63], [64], [65]. These mechanisms have been complemented by mounting evidence, showing patients with liver cirrhosis to exhibit a chronic systemic inflammation with episodic bursts, which exacerbates upon acute decompensation and development of acute-on-chronic liver failure (ACLF) [61,66,67]. Systemic inflammation is strongly associated with disease severity and patient's overall survival and has since been proposed as a main driver for development of complications and organ dysfunctions [61,[66], [67], [68], [69], [70], [71]]. Although it remains undisputed that hemodynamical factors importantly contribute to primal hepatorenal dysfunction, the ‘systemic inflammation hypothesis’ has since introduced immunopathologic tissue damage, inflammation-associated mitochondrial dysfunction, and immune-mediated metabolic disruption into the multifactorial equation, complementing traditionally known mechanisms [67,[72], [73], [74], [75]].
In recent years, a plethora of inflammatory cytokines has been established as a hallmark for decompensated liver cirrhosis and ACLF [71]. In this review, we propose a novel hypothesis to translate established knowledge derived from a robust corpus of data on biglycan in matrix biology to a potential regulator in decompensated liver cirrhosis. Inflammation and autophagy are crucial processes deciding about hepatic and renal disease outcome in hepatorenal dysfunction [66,67,71,[77], [78], [79], [80]]. Therefore, it is possible that biglycan, produced by the cirrhotic liver, represent a missing link in hepatorenal crosstalk. Here we discuss a novel concept, in which biglycan acts as a potential messenger circulating between liver and kidney, and drives inflammation and autophagy, thus deciding about the fate of both organs (Figure 1).
Section snippets
Complexity of biglycan signaling in inflammation and autophagy
The complexity of biglycan signaling in inflammation involves selective interactions with TLR2 and/or TLR4, their co-receptors CD14 and CD44 [9,10,36,4952,[55], [56], [57],76], and their adaptor molecules the myeloid differentiation primary response 88 (MyD88) or Toll/IL-1R domain-containing adapter-inducing interferon (IFN)-β (TRIF) [77]. The details are described in various timely reviews [2,3,57,[78], [79], [80], [81]].
It is of note that, acting as canonical DAMP, biglycan can also trigger
Role of biglycan and autophagy in shaping liver injury
Liver injury results in biglycan synthesis by non-parenchymal liver cells, such as hepatic stellate cells (HSCs) [82,83]. Immuno-histochemical staining of human liver biopsy specimens from patients with active chronic hepatitis B have detected strongly increased biglycan deposits in areas of fibrosis, as well as in the space of Disse, around small bile ducts, and in blood vessel walls [83,84]. Interestingly, a strong association of histopathological necroinflammation and biglycan secretion in
Interplay between biglycan, autophagy and inflammation in shaping renal injury
The crucial role of biglycan in the regulation of renal inflammation and autophagy is firmly established and has been documented in various recent review papers [2,3,79,111,48]. Thus, it is conceivable that extensive biglycan production in liver cirrhosis leads to enhanced plasma levels of biglycan. Circulating biglycan reaches the kidney and results in uncontrolled inflammation, which overrules the protective effects of autophagy and causes renal failure.
Autophagy, which is upregulated in
Hepatic biglycan overexpression in the transgenic pLIVE model and its implications on hepatorenal crosstalk
By using a transgenic pLIVE in vivo model, soluble biglycan, which is strongly increased in patients with manifest liver cirrhosis, has been shown to be an important regulator of autophagy and inflammation in the kidney [36,56]. This pLIVE model induces overexpression of biglycan under the control of an albumin promotor specifically in the liver [50,77]. Thereby, the model mimics the hepatic biglycan overexpression and release of soluble biglycan to the plasma, which is seen in liver cirrhosis.
Soluble biglycan as a messenger between liver and kidney in liver disease
Indeed, data generated in experimental and human liver disease promote the concept of biglycan as a potential messenger between liver and kidney in hepatorenal dysfunction. In various hepatic injury models, elevated levels of circulating SLRPs and their bioactive fragments, specifically biglycan, have been described [85,139,140]. Since SLPRs play a critical role in ECM assembly by regulating fibril growth and organization, these findings have been adjudicated to injury-mediated scar tissue
Conclusions and future perspectives
The ECM-derived proteoglycan biglycan has been identified as a potent activator of sterile inflammation or autophagy in the kidney by interaction with TLR2/4-CD14 or TLR4/CD44, respectively (Fig. 1). Autophagy is implicated in various renoprotective pathways in acute kidney injury and has been confirmed in its therapeutic utility in different renal disease models. In chronic liver disease, biglycan has been evaluated and utilized as a non-invasive fibrosis marker for many years. Interestingly,
Declaration of Competing Interest
The authors declare no conflicts of interest.
Abbreviations
ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; ATG, autophagy-related; CCL, C-C motif ligand; DAMP, danger-associated molecular pattern; ECM, extracellular matrix; HIF-2α, hypoxia-inducible factor 2α; HREs, hypoxia-responsive elements; HSCs, hepatic stellate cells; IL, Interleukin; IRI, renal ischemia/reperfusion injury; LC3, microtubule-associated protein 1A/1B-light chain 3; MDBs, Mallory-Denk bodies; MyD88, Myeloid Differentiation primary response; NAC, N-acetylcysteine;
Acknowledgments
This work was supported by the German Research Council: SFB 1039, project B02, SFB 1177, 259130777, project E02, SCHA 1082/6-1, all to LS; and the Cardio-Pulmonary Institute (CPI), EXC 2026, Project ID: 390649896 (to LS and MW); WY119/1-3 (to MW), the Else Kröner-Fresenius-Foundation (to MW), and the German Center for Lung Research (to MW); European Union's Horizon 2020 research and innovation program's MICROBPREDICT study (No 825694), European Union's Horizon 2020 Research and Innovation
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