The mechanisms linking immune responses and inflammation with tumor development are not well understood. Here we show that the soluble form of the extracellular matrix proteoglycan decorin controls inflammation and tumor growth through PDCD4 (programmed cell death 4) and microRNA (miR) 21 by two mechanisms. First, decorin acted as an endogenous ligand of Toll-like receptor-2 and −4 and stimulated production of proinflammatory molecules, including PDCD4, in macrophages. Second, decorin prevented translational repression of PDCD4 by decreasing the activity of transforming growth factor (TGF) β1 and the abundance of oncogenic miR-21, a translational inhibitor of PDCD4. Moreover, increased PDCD4 resulted in decreased release of the anti-inflammatory cytokine interleukin-10, thereby making the cytokine profile more proinflammatory. This pathway operates in both pathogen-mediated and sterile inflammation as shown here for sepsis and growth retardation of established tumor xenografts. In sepsis, decorin is an early response gene evoked by septic inflammation and decorin concentrations were increased in plasma of septic patients and mice. In cancer, decorin mediated the reduced abundance of anti-inflammatory molecules and increased that of pro-inflammatory molecules, thereby shifting the immune response to a more proinflammatory state that was associated with reduced tumor growth. Thus, by stimulating pro-inflammatory PDCD4 and decreasing the abundance of miR-21, decorin signaling boosts inflammatory activity in sepsis and suppresses tumor growth.

Matrix-bound constituents, such as the small leucine-rich proteoglycan biglycan, can act as powerful signaling molecules when released by limited proteolysis of the extracellular matrix or de novo synthesized by macrophages in the circulation and body fluids. Specifically, biglycan acts as an endogenous ligand of innate immunity by directly engaging the Toll-like receptor (TLR)-2 and -4. In this study, we generated a transient transgenic mouse model where biglycan was de novo overproduced by hepatocytes driven by the albumin promoter. Transgenic biglycan was rapidly and abundantly synthesized by hepatocytes and released into the bloodstream. Notably, we found that circulating biglycan accumulated in the kidneys where it caused recruitment of leukocytes infiltrating the renal parenchyma concurrent with abnormal renal levels of chemoattractants CXCL1, CXCL2, CCL2 and CCL5. Using mice deficient in either TLR adapter proteins MyD88 or TRIF we discovered that MyD88 deficiency drastically reduced neutrophil and macrophage infiltration in the kidney, whereas TRIF deficiency decreased T cell infiltrates. Production of CXCL1, CXCL2 and CCL2 required MyD88, whereas the levels of T cell and macrophage attractant CCL5 required TRIF. Thus, we provide robust genetic evidence for circulating biglycan as a powerful pro-inflammatory mediator targeting the renal parenchyma. Furthermore, our results provide the first evidence that biglycan differentially triggers chemoattraction of leukocytes via two independent pathways, both under the control of TLR2/4, utilizing either MyD88 or TRIF adaptor proteins. As aberrant expression of biglycan occurs in several inflammatory diseases, this transient transgenic mouse model could serve as a valuable research tool in investigating the effects of increased biglycan expression in vivo and for the development of therapeutic strategies in the treatment of inflammatory diseases.

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Acetylcholine (ACh) is not only a neurotransmitter but is an ancient molecule that can be released by and act on non-neuronal cells. In these cells the system of ACh-synthesizing enzymes, transporters, receptors and degrading enzymes is termed the non-neuronal cholinergic system (NNCS). There is increasing evidence that the NNCS is dysregulated in various diseases and can have an influence on their pathology. However, for many organ systems not much is known about the expression and function of the NNCS. Thus, this review focusses on the role of the NNCS in different organ systems in health and disease. Dysregulation of ACh synthesis and release, mutations or polymorphisms in genes encoding NNCS components, and auto-antibodies against NNCS components are common factors influencing disease progression. Pharmacological agents targeting the NNCS are already successfully in clinical use for some disorders, indicating that interfering with this system is very promising and more research is needed to elucidate the role of the NNCS in different tissues and pathological states.

No abstract