Differential roles for NOD2 in osteoblast inflammatory immune responses to bacterial pathogens of bone tissue

Osteoblasts produce an array of immune molecules following bacterial challenge that can contribute to inflammation and the recruitment of leukocytes to sites of infection during bone diseases such as osteomyelitis. However, the mechanisms by which osteoblasts perceive and respond to facultative intracellular pathogens such as Salmonella species and Staphylococcus aureus have not been determined. Recently, our laboratory has described the expression in osteoblasts of members of the nucleotide-binding domain leucine-rich repeat region containing family of proteins that include nucleotide-binding oligomerization domain-2 (NOD2), a molecule that functions as an intracellular receptor for bacterial peptidoglycans. In the present study, we demonstrate that NOD2 expression is required for select inflammatory mediator production by osteoblasts following infection with the invasive pathogen Salmonella. In contrast, we have found that the inflammatory immune responses of osteoblasts to the passively internalized bacterial species Staphylococcus aureus, heat-killed pathogenic Salmonella, a non-invasive Salmonella strain and specific Toll-like receptor ligands are not reduced in the absence of NOD2 expression but are, in fact, elevated. Based upon these findings, we suggest that NOD2 serves differential roles in osteoblasts, promoting inflammatory responses to invasive bacteria while tempering cell responses to extracellular and/or passively internalized bacterial species.