Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney

Nastase, Madalina V.; Zeng-Brouwers, Jinyang; Beckmann, Janet; Tredup, Claudia; Christen, Urs; Radeke, Heinfried H.; Wygrecka, Małgorzata; Schaefer, Liliana

doi:10.1016/j.matbio.2017.12.002

Cited by 43 publications

(58 citation statements)

References 78 publications

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“…Furthermore, Myd88 is required, at least in part, for spontaneous production of IL-6, MCP-1, and TNFα within the salivary tissue. Importantly, numerous studies show Myd88 is essential for DAMP-mediated inflammation (44,60,69,70). Our findings suggest that the attenuated disease phenotype observed in the Myd88 −/− NOD.B10 model may be due to reduced activation of DAMPmediated TLR signaling networks (9).…”

Section: Discussionmentioning

confidence: 58%

“…These DAMPs could then bind to TLRs expressed by salivary gland epithelial cells and tissue resident immune populations, thereby driving production of pro-inflammatory mediators and facilitating the recruitment of innate and adaptive cells into the salivary tissue (59). This paradigm is supported by studies of kidney pathoses, as DAMP-mediated recruitment of Th1 and Th17 cells is mediated by TLR2 and TLR4 interactions (60). Since most cells recruited to the salivary tissue express TLRs (8), this may lead to a continuous cycle of unremitting inflammation and further tissue destruction.…”

Section: Discussionmentioning

confidence: 98%

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Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

et al. 2020

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Toll-like receptors (TLRs) are important mediators of chronic inflammation in numerous autoimmune diseases, although the role of these receptors in primary Sjögren's syndrome (pSS) remains incompletely understood. Previous studies in our laboratory established Myd88 as a crucial mediator of pSS, although the disease-relevant ligands and the upstream signaling events that culminate in Myd88 activation have yet to be established. The objective of this study was to identify specific Myd88-dependent TLR-related pathways that are dysregulated both locally and systemically in a mouse model of pSS [NOD.B10Sn-H2 b /J (NOD.B10)]. We performed RNA-sequencing on spleens derived from NOD.B10 mice. We then harvested salivary tissue and spleens from Myd88-sufficient and deficient C57BL/10 (BL/10) and NOD.B10 mice and performed flow cytometry to determine expression of Myd88-dependent TLRs. We cultured splenocytes with TLR2 and TLR4 agonists and measured production of inflammatory mediators by ELISA. Next, we evaluated spontaneous and TLR4-mediated inflammatory cytokine secretion in NOD.B10 salivary tissue. Finally, we assessed spontaneous Myd88-dependent cytokine secretion by NOD.B10 salivary cells. We identified dysregulation of numerous TLR-related networks in pSS splenocytes, particularly those employed by TLR2 and TLR4. We found upregulation of TLRs in both the splenic and salivary tissue from pSS mice. In NOD.B10 splenic tissue, robust expression of B cell TLR1 and TLR2 required Myd88. Splenocytes from NOD.B10 mice were hyper-responsive to TLR2 ligation and the endogenous molecule decorin modulated inflammation via TLR4. Finally, we observed spontaneous secretion of numerous inflammatory cytokines and this was enhanced following TLR4 ligation in female NOD.B10 salivary tissue as compared to males. The spontaneous production of salivary IL-6, MCP-1 and TNFα required Myd88 in pSS salivary tissue. Thus, our data demonstrate that Myd88-dependent TLR pathways contribute to the inflammatory landscape in pSS, and inhibition of such will likely have therapeutic utility.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 98%

Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

et al. 2020

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“…Lately new findings have emerged supporting these observations [19,24]. It has been reported that biglycan can also limit inflammation by dampening the synthesis of IL-1b in a NOX2-dependent manner [20].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 91%

“…Recently it was shown that plasma levels of a soluble biglycan correlate with CXCL10 and CXCL9 in patients with LN [19]. Following these findings, LN in biglycan-overexpressing and biglycan-deficient mice revealed that biglycan mediates a crosstalk between macrophages, Th1 and Th17 cells [19]. By autonomously signaling through TLR4/TRIF, biglycan induces CXCL10 production in macrophages while CXCL9 is triggered in synergy with interferone (IFN)c by biglycan.…”

Section: Biglycan In Autoimmune Diseasesmentioning

confidence: 99%

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

et al. 2019

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It is well established that biglycan, a small leucine‐rich proteoglycan, acts as an extracellular matrix‐derived danger signal in its soluble form. By binding to innate immunity Toll‐like receptors (TLR) 2 and 4, biglycan initiates and perpetuates the inflammatory response. Previous work has conveyed that biglycan's role in inflammation extends far beyond its function as a canonical danger signal. It has been shown that biglycan acts in an anti‐inflammatory capacity, wherein it tightly regulates the inflammatory response. In this review, we will discuss a paradigm shift to our understanding of biglycan signaling in inflammation. Mounting evidence suggests that the selective interactions between biglycan, TLRs, and their adapter proteins critically regulate downstream signaling and disease outcome. Biglycan can act as a high‐affinity ligand for TLR coreceptors CD14 and CD44, further providing an additional layer of complexity. We propose a novel concept, that biglycan steers signaling toward inflammation by interacting with CD14, whereas it can trigger autophagy by binding to CD44. Thus, biglycan, and perhaps others soluble proteoglycans, could function as molecular switches which could either propagate the signaling of chronic inflammation or promote the resolution of inflammatory processes. Obviously, these new functions have broad implications in the regulation of various inflammatory diseases and could provide the basis for developing novel therapeutic regimens that would selectively target the interactions between biglycan, TLRs, coreceptors, and adapter molecules.

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“…In transplant-associated renal ischemia/ reperfusion injury, TGF-b1 initiates early repair and regeneration but in the setting of chronic inflammation drives continual matrix deposition and remodeling, leading to fibrotic disease, compromised renal function, and eventual organ rejection (46). Excessive ECM accumulation also provides a source of damage-associated molecular pattern ligands for the inflammatory response TLR (47)(48)(49)(50). Progressive fibrosis, moreover, leads to enhanced tissue stiffness.…”

Section: The Renal Fibrotic Microenvironmentmentioning

confidence: 99%

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

et al. 2019

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Chronic kidney disease affects >15% of the U.S. population and >850 million individuals worldwide. Fibrosis is the common outcome of many chronic renal disorders and, although the etiology varies (i.e., diabetes, hypertension, ischemia, acute injury, and urologic obstructive disorders), persistently elevated renal TGF‐β1 levels result in the relentless progression of fibrotic disease. TGF‐β1 orchestrates the multifaceted program of renal fibrogenesis involving proximal tubular dysfunction, failed epithelial recovery and redifferentiation, and subsequent tubulointerstitial fibrosis, eventually leading to chronic renal disease. Recent findings implicate p53 as a cofactor in the TGF‐β1‐induced signaling pathway and a transcriptional coregulator of several TGF‐β1 profibrotic response genes by complexing with receptor‐activated SMADs, which are homologous to the small worms (SMA) and Drosophilia mothers against decapentaplegic (MAD) gene families. The cooperative p53‐TGF‐β1 genomic cluster includes genes involved in cell growth control and extracellular matrix remodeling [e.g., plasminogen activator inhibitor‐1 (PAI‐1; serine protease inhibitor, clade E, member 1), connective tissue growth factor, and collagen I]. Although the molecular basis for this codependency is unclear, many TGF‐β1‐responsive genes possess p53 binding motifs. p53 up‐regulation and increased p53 phosphorylation; moreover, they are evident in nephrotoxin‐ and ischemia/reperfusion‐induced injury, diabetic nephropathy, ureteral obstructive disease, and kidney allograft rejection. Pharmacologic and genetic approaches that target p53 attenuate expression of the involved genes and mitigate the fibrotic response, confirming a key role for p53 in renal disorders. This review focuses on mechanisms whereby p53 functions as a transcriptional regulator within the TGF‐β1 cluster with an emphasis on the potent fibrosis‐promoting PAI‐1 gene.—Higgins, C. E., Tang, J., Mian, B. M., Higgins, S. P., Gifford, C. C., Conti, D. J., Meldrum, K. K., Samarakoon, R., Higgins, P. J. TGF‐β1‐p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications. FASEB J. 33, 10596–10606 (2019). http://www.fasebj.org

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Biglycan, a novel trigger of Th1 and Th17 cell recruitment into the kidney

Cited by 43 publications

References 78 publications

Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

Activation of Myd88-Dependent TLRs Mediates Local and Systemic Inflammation in a Mouse Model of Primary Sjögren's Syndrome

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

TGF‐β1–p53 cooperativity regulates a profibrotic genomic program in the kidney: molecular mechanisms and clinical implications

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