Small Leucine-Rich Proteoglycans in Renal Inflammation: Two Sides of the Coin

Abstract

It is now well-established that members of the small leucine-rich proteoglycan (SLRP) family act in their soluble form, released proteolytically from the extracellular matrix (ECM), as danger-associated molecular patterns (DAMPs). By interacting with Toll-like receptors (TLRs) and the inflammasome, the two SLRPs, biglycan and decorin, autonomously trigger sterile inflammation. Recent data indicate that these SLRPs, besides their conventional role as pro-inflammatory DAMPs, additionally trigger anti-inflammatory signaling pathways to tightly control inflammation. This is brought about by selective employment of TLRs, their co-receptors, various adaptor molecules, and through crosstalk between SLRP-, reactive oxygen species (ROS)-, and sphingolipid-signaling. In this review, the complexity of SLRP signaling in immune and kidney resident cells and its relevance for renal inflammation is discussed. We propose that the dichotomy in SLRP signaling (pro- and anti-inflammatory) allows for fine-tuning the inflammatory response, which is decisive for the outcome of inflammatory kidney diseases.

Decorin‐mediated oncosuppression – a potential future adjuvant therapy for human epithelial cancers

“…This is achieved by inducing the expression of cyclin‐dependent kinase inhibitors p21 Waf‐1 and p27 Kip‐1 , without any interaction with EGF receptors (Xaus et al, ). Also in inflammatory and fibrotic kidney diseases, decorin suppressed inflammation through its binding and neutralizing of the activity of the pro‐fibrotic factor TGF‐β (Nastase et al, ). Furthermore, decorin interaction with EGFRs and IGF‐IRs was demonstrated to play a beneficial role in the pathogenesis of kidney diseases (Nastase et al, ).…”

“…Also in inflammatory and fibrotic kidney diseases, decorin suppressed inflammation through its binding and neutralizing of the activity of the pro‐fibrotic factor TGF‐β (Nastase et al, ). Furthermore, decorin interaction with EGFRs and IGF‐IRs was demonstrated to play a beneficial role in the pathogenesis of kidney diseases (Nastase et al, ). Contrasting effect was observed in chronic pancreatitis, where decorin is highly expressed in the stroma by activated pancreatic stellate cells (Köninger et al, ).…”

Proteoglycans in Biomedicine: Resurgence of an Underexploited Class of ECM Molecules

“…By far the most widely researched class of PGs, SLRPs share structural similarities in their core protein of leucine rich tandem repeats flanked by cysteine rich repeats. The biological functions of SLRPs are too vast to be summarized in a single review, hence, we refer readers to recent comprehensive reviews focusing specifically on SLRPs (Iozzo, 1997;Iozzo, 1999;Schaefer and Iozzo, 2008;Chen and Birk, 2013;Hultgårdh-Nilsson et al, 2015;Nastase et al, 2018;Appunni et al, 2019). It is widely accepted that the horseshoe-shaped core protein of SLRPs is responsible for its binding to collagen, modulating collagen fibrillogenesis and protecting collagen from enzymatic cleavage (Karamanos et al, 2018).…”

“…Decorin is the archetypal, most extensively studied SLRP, and has been vastly characterized for its influence on collagen fibrillogenesis (Danielson et al, 1997) and involvement in scarless wound healing. Decorin is not just a structural entity, it plays a pivotal biological role in angiogenesis (Järveläinen et al, 2015), inflammation (Nastase et al, 2018), fibrosis (Ahmed et al, 2014), wound healing (Grisanti et al, 2005), oncosuppression (Sainio and Järveläinen, 2019), and endothelial cell health and autophagy (Neill et al, 2017) to name some. Due to this involvement in an enormous range of biological functions, decorin has aptly been termed as a "guardian from the matrix" (Neill et al, 2012).…”

Breaking down chronic inflammatory diseases: the role of biglycan in promoting a switch between inflammation and autophagy

“…In the last decades the research in the ECM field underlined the functional complexity of certain SLRPs being recognized as dual molecules: tissue organizers and signaling Abbreviations apoB, apolipoprotein B; BMP, bone morphogenetic protein; CAVD, calcific aortic valve disease; CCL, chemokine (C-C motif) ligand; CD, cluster of differentiation; CXCL, chemokine (C-X-C motif) ligand; CXCR, chemokine (C-X-C) motif receptor; DAMP, damage-associated molecular pattern; DN, diabetic nephropathy; ECM, extracellular matrix; Erk, extracellular signal-regulated kinase; GAG, glycosaminoglycan; HSP, heat shock protein; IL, interleukin; IRI, ischemia/reperfusion injury; LDL, low-density lipoprotein; LN, lupus nephritis; MyD88, adaptor molecule myeloid differentiation primary response gene 88; NF-jB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOX, NADPH oxidase; SLRP, small leucine-rich proteoglycan; TGF-b, transforming growth factor-b; TLR, Toll-like receptors; TNF-a, tumor necrosis factor alpha; TRIF, TIR domain-containing adapter inducing interferon-b; VICs, valve interstitial cells. molecules [1][2][3][4]. Biglycan is one of the best characterized signaling SLRP, modulating various pathways dependent on, for example, Toll-like receptors (TLR) 2/4 [5], transforming growth factor (TGF)-b1-ALK5 [6], bone morphogenetic protein (BMP) [7][8][9], or Wnt3a/LRP6 [10].…”