PMID- 37191536 OWN - NLM STAT- MEDLINE DCOM- 20230619 LR - 20231120 IS - 2165-0497 (Electronic) IS - 2165-0497 (Linking) VI - 11 IP - 3 DP - 2023 Jun 15 TI - Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion. PG - e0429322 LID - 10.1128/spectrum.04293-22 [doi] LID - e04293-22 AB - Belonging to a group of membrane proteins, bacterial lipoproteins (LPPs) are defined by a unique lipid structure at their N-terminus providing the anchor in the bacterial cell membrane. In Gram-positive bacteria, LPPs 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 demonstrate that Staphylococcus aureus Lpl1 not only triggers cytokine production but also confers a shift toward fermentative metabolism in bone marrow-derived macrophages (BMDMs). Lpl1 consists of di- and tri-acylated LPP variants; hence, the synthetic P2C and P3C, mimicking di-and tri-acylated LPPs, were employed to reveal their effect on BMDMs. Compared to P3C, P2C was found to shift the metabolism of BMDMs and the human mature monocytic MonoMac 6 (MM6) cells more profoundly toward 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 than 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 toward fermentation, and ensuing bone destruction. IMPORTANCE Osteomyelitis caused by S. aureus is a severe infection of the bone, typically associated with severe bone function impairment, therapeutic failure, high morbidity, invalidity, and occasionally even death. The hallmark of staphylococcal osteomyelitis is the destruction of the cortical bone structures, yet the mechanisms contributing to this pathology are hitherto poorly understood. One bacterial membrane constituent found in all bacteria is bacterial lipoproteins (LPPs). Previously, we have shown that injection of purified S. aureus LPPs into wild-type mouse knee joints caused a TLR2-dependent chronic destructive arthritis but failed to elicit such effect in monocyte/macrophage-depleted mice. This observation stirred our interest in investigating the interaction of LPPs and macrophages and analyzing the underlying physiological mechanisms. This ascertainment of LPP-induced changes in the physiology of macrophages provides an important clue in the understanding of the mechanisms of bone disintegration, opening novel avenues to manage the course of S. aureus disease. FAU - Nguyen, Minh-Thu AU - Nguyen MT AUID- ORCID: 0000-0001-6510-0684 AD - Institute of Medical Microbiology, University Hospital Munster, Munster, Germany. FAU - Hu, Zhicheng AU - Hu Z AUID- ORCID: 0000-0002-3899-0711 AD - Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, China. AD - Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Mohammad, Majd AU - Mohammad M AUID- ORCID: 0000-0002-3672-2991 AD - Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Schottler, Hannah AU - Schottler H AD - Institute of Inorganic and Analytical Chemistry, University of Munster, Munster, Germany. FAU - Niemann, Silke AU - Niemann S AD - Institute of Medical Microbiology, University Hospital Munster, Munster, Germany. FAU - Schultz, Michelle AU - Schultz M AD - Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Barczyk-Kahlert, Katarzyna AU - Barczyk-Kahlert K AD - Institute of Immunology, University of Munster, Munster, Germany. FAU - Jin, Tao AU - Jin T AUID- ORCID: 0000-0001-9039-0628 AD - Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. FAU - Hayen, Heiko AU - Hayen H AUID- ORCID: 0000-0002-4074-8545 AD - Institute of Inorganic and Analytical Chemistry, University of Munster, Munster, Germany. FAU - Herrmann, Mathias AU - Herrmann M AD - Institute of Medical Microbiology, University Hospital Munster, Munster, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230516 PL - United States TA - Microbiol Spectr JT - Microbiology spectrum JID - 101634614 RN - 0 (Toll-Like Receptor 2) RN - 0 (Cytokines) RN - 0 (Lipoproteins) RN - 0 (Bacterial Proteins) SB - IM MH - Animals MH - Mice MH - Humans MH - *Toll-Like Receptor 2/metabolism MH - Staphylococcus aureus/metabolism MH - Macrophages MH - Cytokines/metabolism MH - Glycolysis MH - Lipoproteins/metabolism MH - *Osteomyelitis MH - Bacterial Proteins/metabolism PMC - PMC10269925 OTO - NOTNLM OT - Pam2Cys OT - Pam3Cys OT - bacterial lipoprotein OT - bone erosion OT - bone marrow-derived macrophages OT - cellular metabolism OT - lactate COIS- The authors declare no conflict of interest. EDAT- 2023/05/16 13:09 MHDA- 2023/06/19 13:08 PMCR- 2023/05/16 CRDT- 2023/05/16 10:09 PHST- 2023/06/19 13:08 [medline] PHST- 2023/05/16 13:09 [pubmed] PHST- 2023/05/16 10:09 [entrez] PHST- 2023/05/16 00:00 [pmc-release] AID - 04293-22 [pii] AID - spectrum.04293-22 [pii] AID - 10.1128/spectrum.04293-22 [doi] PST - ppublish SO - Microbiol Spectr. 2023 Jun 15;11(3):e0429322. doi: 10.1128/spectrum.04293-22. Epub 2023 May 16.