Open Access

Rosetta Merline

• Decorin, a small leucine rich proteoglycan (SLRP) of the extracellular matrix (ECM) is a biologically active molecule with signaling capabilities modulating diverse cellular functions 1. In this report, we explore the role of the matrix proteoglycan decorin in the regulation of inflammation and apoptosis and the resultant biological significance in cancer and diabetic nephropathy. The mechanisms linking immunity and inflammation with tumor development are not well defined. Here we report a novel finding that the soluble form of decorin could autonomously trigger the synthesis of TNFα and IL-12 in macrophages through TLR2 and TLR4 in a p44/42- and p38-dependent manner. In the presence of LPS, decorin enhanced the effects of LPS by signaling additionally via TLR2. Further, decorin could enhance PDCD4 protein expression with subsequent inhibition of LPS-mediated IL-10 protein synthesis by two mechanisms: i) by TLR2/TLR4-dependent stimulation of PDCD4 synthesis and ii) by inhibition of the TGFβ1-induced increase of miR-21, a posttranscriptional suppressor of PDCD4 protein synthesis. Enhanced PDCD4, a translational inhibitor of IL-10, downregulated this anti-inflammatory cytokine, thereby further driving the cytokine profile towards a proinflammatory phenotype. Importantly, these mechanisms appear to operate in a broad biological context linking pathogen-mediated with sterile inflammation as shown here for sepsis and growth retardation of established tumor xenografts. In sepsis, decorin is an early response gene evoked by inflammation and is markedly elevated in plasma of septic human patients and in plasma and tissues of septic mice. Our findings suggested that in vivo decorin alone mimics the effects of LPS by enhancing the plasma and tissue levels of pro-inflammatory TNFα, IL-12 and PDCD4 but when administered together with LPS, it potentiated the proinflammatory response of this PAMP by inhibiting active TGFβ1, miR-21 and hence the LPS mediated IL-10 production. In vivo, overexpression of decorin in tumor xenografts resulted in decorin/TLR2/4-driven synthesis of PDCD4, TNFα, IL-12 and decorin/TGFβ1/miR-21-mediated inhibition of PDCD4 suppression shifting the immune response to a pro-apoptotic and proinflammatory axis with strong anti-tumorigenic effects resulting in increased apoptosis and growth retardation of solid tumor. Thus, decorin signaling boosts inflammatory activity in sepsis and tumor. In contrast to the proinflammatory and proapoptotic role of decorin in tumor, decorin deficiency in diabetic kidneys led to enhanced apoptosis and increased mononuclear cell infiltration indicating that decorin might give rise to distinct biological outcomes depending on the cell type and biological context. Accordingly, in this study, we used a model of streptozotocin-induced diabetes type 1 in wild-type (Dcn+/+) and decorin-deficient- (Dcn-/-) mice to further elucidate the role of decorin in diabetic nephropathy. In this model, decorin was overexpressed in the mesangial matrix of the glomerulus and in the tubulointerstitium both at the mRNA and protein level in early stages of diabetic nephropathy which declined as the disease further progressed supporting the concept that decorin might act as a part of a natural response to hyperglycemia and to damage caused there from. These observations correlate with the data obtained in renal biopsies from patients at various stages of diabetic nephropathy 15, suggesting clinical relevance of our findings for the human disease. In the diabetic kidney, decorin deficiency was associated with: i) glomerular and tubular overexpression of p27Kip1 and enhanced proteinuria, ii) enhanced expression of TGFβ1 and CTGF resulting in increased accumulation of ECM, iii) overexpression of biglycan and elevated infiltration of mononuclear cells, iv) enhanced apoptosis of tubular epithelial cells despite overexpression of tubular IGF-IR. We further discovered that decorin binds to the IGF-IR in tubular epithelial cells and conveys protection against high glucose-mediated apoptosis providing evidence for a protective role of decorin during diabetic nephropathy development. Thus, future therapeutic approaches that would either enhance the endogenous production of decorin or deliver exogenous decorin to the diseased solid tumors and/or diabetic kidney might improve the prognosis of these chronic diseases.
• Die vorliegende Arbeit beschäftigt sich mit: i) den signalübertragenden Eigenschaften von Decorin, ii) der Charakterisierung von decorinbindenden Rezeptoren (Rezeptoren der angeborenen Immunität: Toll-like Rezeptoren 2/4 und Insulin-like Growth Faktor-I Rezeptor), iii) down-stream Mediatoren und iv) den biologischen Konsequenzen von decorininduziertem Signaling auf die pathogenvermittelte Entzündung (Sepsis) und „sterile“ Inflammation (Diabetische Nephropathie und Tumorwachstum). Decorin ist ein kleines, leuzinreiches Proteoglycan der extrazellulären Matrix. Es besteht aus einem Proteinkern mit leuzinreichen Wiederholungseinheiten (LRR) und einer kovalent gebundenden Glycosaminoglycan-Seitenkette aus Chondroitin- oder Dermatansulfat. Diese strukturelle Diversität sowie die perizelluläre Lokalisation ermöglichen Decorin Signalfunktionen auszuüben und somit Zellfunktionen zu beeinflussen. Es ist bekannt, dass Decorin eine Reihe von Wachstumsfaktoren beeinflussen kann, welche potenziell in der Regulation des Immunsystems involviert sind 2-6. Die Signalmechanismen und biologische Relevanz von Decorin für die Regulation von Entzündungsreaktionen sind hingegen noch nicht ausreichend untersucht worden. Dahingehend sollte die Rolle von Decorin in der Pathophysiologie der bakteriellen Sepsis untersucht werden. Hier konnte ein erhöhtes Vorkommen von zirkulierendem Decorin in Plasmaproben von männlichen und weiblichen septischen Patienten beobachtet werden, was darauf hinweist, dass Decorin ein wichtiges Protein in der Entzündungsreaktion sein könnte, dessen Expression in der frühen Phase einer systemischen Entzündung heraufreguliert wird. Desweiteren wurde experimentell durch Injektion von LPS eine Sepsis in Dcn+/+ und Dcn-/- Mäusen induziert. Analog zu den Befunden im humanen System zeigten die Dcn+/+ Mäuse eine frühe Erhöhung von Decorin in der Zirkulation. Zudem konnte vermehrt Dcn mRNA und Protein in der septischen Lunge, einem der wichtigsten Zielorgane in der murinen Sepsis, detektiert werden. In vitro zeigten LPS-stimulierte peritoneale Macrophagen nach 30 min eine vermehrte Expression von Dcn mRNA sowie von sekretiertem Proteoglykan im Überstand...