Bacterial lipoproteins shift cellular metabolism to glycolysis in macrophages causing bone erosion

Belonging to a group of membrane proteins, bacterial lipoproteins (LPP) are defined by a unique lipid structure at their N-terminus providing the anchor in the bacterial cell membrane. In Gram-positive bacteria, LPP play a key role in host immune activation triggered through a Toll-like receptor 2 (TLR2)-mediated action resulting in macrophage stimulation and subsequent tissue damage demonstrated in in vivo experimental models. Yet, the physiologic links between LPP activation, cytokine release, and any underlying switches in cellular metabolism remain unclear. In this study, we demonstrated that S. aureus Lpl1 not only triggers cytokine production but also confers a shift towards fermentative metabolism in bone marrow derived macrophages (BMDM). Lpl1 consists of di- and tri-acylated LPP variants, hence, the synthetic P2C and P3C, mimicking di-and tri-acylated LPP, were performed to reveal their effect on BMDM. When compared to P3C, P2C was found to shift the metabolism of BMDM and the human mature monocytic MonoMac 6 (MM6) cells more profoundly towards the fermentative pathway as indicated by lactate accumulation, glucose consumption, pH reduction, and oxygen consumption. In vivo, P2C caused more severe joint inflammation, bone erosion and lactate and malate accumulation when compared to P3C. These observed P2C effects were completely abrogated in monocyte/macrophage depleted mice. Taken together, these findings now solidly confirm the hypothesized link between LPP exposure, a macrophage metabolic shift towards fermentation, and ensuing bone destruction.