Molecular mechanisms of monocyte modulation by soluble proteoglycans and their impact on inflammatory renal diseases

• Applicant: Professorin Dr. Liliana Schaefer
• Subject Area: Nephrology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280926947

More than one in ten adults world wide experience chronic renaldiseases (CKD). This high incidence together with lack of appropriatecurative treatments, call for the development of novel therapeuticstrategies. Deregulated sterile inflammation and accumulation ofextracellular matrix (ECM) are important triggers of renal fibrogenesisand components of chronic renal diseases. So far, the mechanismsresponsible for switching sterile inflammation to resolution orchronification have remained elusive. Monocytes from peripheralblood as precursor cells of renal macrophages and dendritic cells arepotential crucial regulators of inflammatory kidney diseases. Notably,there is mounting evidence linking the severity of infectious and sterileinflammation to enhanced number of proinflammatory bloodmonocytes, mostly comprised of intermediate and non-classicalmonocytes. However the mechanisms triggering the monocyte switchfrom classical to intermediate and non-classical subsets remainelusive. Despite of potential importance of monocytes in theregulation of CKD data regarding the role of monocyte-subtypes atthe onset of inflammatory renal diseases and their impact on diseasechronification are missing. In previous studies, the PI laboratory hasdiscovered that two soluble proteoglycans, biglycan and decorin, actas endogenous ligands of innate immunity receptors Toll-like receptor(TLR)4 and TLR2. Furthermore, we detected soluble biglycan in theserum of patients with infectious and sterile inflammation. Our newpreliminary data indicate that biglycan influences monocytephenotypes by interacting with CD14, an adaptor molecule of TLR2/4,thereby inducing a shift towards intermediate and non-classicalmonocytes. Based on these novel findings we plan to identify sourcesand biological functions of soluble biglycan/decorin in serum withspecial attention to proteoglycan-induced changes in the phenotypesof monocytes and their impact on renal inflammation and fibrosis. Theultimate goal is to provide a proof-of-principle for novel therapeuticsaimed at controlling chronification of inflammatory renal diseases andfibrosis using neutralizing antibodies/peptides that prevent binding ofbiglycan to CD14/TLR2/4 on monocytes.

• DFG Programme: Research Grants