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.