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 <em>N</em>-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 <em>in vivo</em> 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 <em>S. aureus</em> 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. <em>In vivo</em>, 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.