Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury

Abstract

Exacerbated inflammation in renal ischemia-reperfusion injury, the major cause of intrinsic acute renal failure, is a key trigger of kidney damage. During disease endogenous danger signals stimulate innate immune cells via Toll-like receptor (TLR)-2 and -4 and accelerate inflammatory responses. Here we show that production of soluble biglycan, a small leucine-rich proteoglycan, is induced during reperfusion and that it functions as endogenous agonist of TLR-2/4. Biglycan-mediated activation of TLR-2/4 initiates an inflammatory response in native kidneys, which is marked by the release of cytokines and chemokines and recruitment of inflammatory cells. Overexpression of soluble circulating biglycan proteoglycan before ischemic reperfusion enhanced plasma and renal levels of TNF-α, CXCL1, CCL2 and CCL5, caused influx of neutrophils, macrophages and T cells and overall worsened renal function in wild type mice. We provide robust genetic evidence for TLR-2/4 requirement insofar as biglycan biological effects were markedly dampened in mice deficient in both innate immune receptors, Tlr2−/−;Tlr4−/− mice. Thus, signaling of soluble biglycan via TLR-2/4 could represent a novel therapeutic target for the prevention and possibly treatment of patients with acute renal ischemia-reperfusion injury.

Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation

“…Several studies indicate that versican is a DAMP (dangerassociated molecular pattern) molecule that interacts with TLRs, such as TLR2, to promote production of inflammatory cytokines, such as TNF␣ (56 -64). Similarly, other CS PG ECM molecules, such as biglycan, activate TLR2 and TLR4 via CS chains and core protein, exacerbating acute kidney injury (54,65,66) Overall, these findings suggest that versican may activate TLR-NF-B and/or CD44-EGFR signaling, increasing HA production via Has2, which promotes leukocyte accumulation and helps sustain the inflammatory state. Because HA is also capable of triggering TLR-and CD44-signaling pathways, it is likely that the HA-versican complex may potentiate the binding of the molecules to the cell surface receptors in a synergistic way.…”

Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns

“…In contrast to PAMPs, selected DAMPs have the unique ability to interact with two TLRs, frequently TLR2/4, sensing Gram-positive as well as Gram-negative pathogens. The fact that the affinity binding of two DAMPs, biglycan and decorin, to TLR4 is comparable with those of LPS (14,83) further underscores how powerful these DAMPs are. Thus, it is conceivable that the DAMP-PAMP interaction defines the biological outcome of TLR signaling.…”

Beyond Tissue Injury—Damage-Associated Molecular Patterns, Toll-Like Receptors, and Inflammasomes Also Drive Regeneration and Fibrosis

“…33,37,40,73 Numerous inflammatory and fibrotic kidney disorders are associated with decorin and biglycan induction. 33,37,38,40,57,74,75 . Transient overexpression of soluble biglycan in mice demonstrates that biglycan triggers inflammation in healthy kidneys and potentiates renal inflammation and fibrosis (Table 1).…”

“…Transient overexpression of soluble biglycan in mice demonstrates that biglycan triggers inflammation in healthy kidneys and potentiates renal inflammation and fibrosis (Table 1). 38,[74][75][76] Finally, there is overwhelming evidence for an antifibrotic activity of soluble decorin directly interacting with another crucial members of the TGF-b superfamily, such as connective tissue growth factor (CTGF), and inhibiting apoptosis of renal tubular epithelial cells (TECs) via the IGF type I receptor/Akt-signaling pathway ( Figure 2). 33,48,49,73,77,78 Kidney-Specific Modes of DAMP Generation Tamm-Horsfall protein (renamed uromodulin) is an adhesive, particle-forming protein that is exclusively secreted at the thick ascending limb of the distal tubule.…”