Role of adipocyte TLR7 and TLR9 immuno-metabolic pathways in metaflammation, adipose inflammation and adipocyte autophagy

• Applicant: Professor Dr. Thomas Karrasch
• Subject Area: Endocrinology, Diabetology, Metabolism ; Clinical Immunology and Allergology
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 354216652

In the previous funding period, we found significantly increased TLR7- and TLR9-expression during adipocyte differentiation. Stimulation via specific TLR7- and TLR9-agonists modulated adipo-cytokine expression and secretion as well as the expression of functionally relevant genes in adipocytes. Putative physiologic ligands of TLR7 and TLR9 in vivo are cell-free nucleic acids (cfDNA), which are increased in the systemic circulation in obese patients. Additionally, transcriptome analyses in TLR9wt/wt- versus TLR9-/--adipocytes hinted at a cross-talk of TLR9 signal transduction and adipocyte autophagy, which plays an important role in adipocyte physiology. Our central hypothysis is: TLR7 and TLR9 in adipocytes detect cell-free nucleic acids (cfDNA), impacting on adipocyte autophagy and thereby modulating adipose inflammation locally as well as metaflammation systemically. Our current research proposal combines experiments in cell lines with studies in primary murine and human adipocytes, including additional analyses in a human obese patient cohort and transgenic mice models. Molecular characterization of the interaction between metabolism and the innate immune system (TLRs) holds a great potential for future therapeutic avenues in insulin resistance, obesity and type 2 diabetes mellitus. Based on our results, TLR7/9-agonists and -antagonists might be employed in an anti-inflammatory treatment of metabolic diseases in the future. Ultimate goal of our work is the adipocyte-specific modulation of TLR7/9 signaling.

• DFG Programme: Research Grants