Ramasamy, B. | bioRxiv Science

bioRxiv2026

Human Osteocytes Express MHC ClassII and Act as Non-classical Antigen-Presenting Cells During Bacterial Infection

Osteocytes are the most abundant cells in bone and are increasingly recognised not only for their role in skeletal remodelling and inflammatory signalling but also for their potential involvement in immune responses. In this study, we searched available gene expression datasets of human primary osteocyte-like cells exposed acutely to Staphylococcus aureus and identified significantly induced expression of key genes related to antigen processing and presentation. We then confirmed that human bone explant-derived osteoblastic cells, representative of a mature osteoblast-pre-osteocyte stage, expressed, as expected, high cell surface levels of major histocompatibility complex (MHC) Class I but also, low basal levels of the MHC Class II family member, HLA-DR. However, confocal imaging revealed high expression of MHC Class II molecules and the peptide-loading chaperone HLA-DM within the lysosomal compartments, consistent with canonical antigen-processing machinery. Differentiation towards a mature osteocyte phenotype increased MHC Class II protein levels and maintained expression of intracellular HLA-DM. Exposure of mature osteocyte-like cells to S. aureus further up-regulated both intracellular and cell surface MHC Class II expression. Demonstrative of antigen presenting cell functionality, S. aureus-exposed osteocytes induced autologous CD4+ T cell proliferation. Furthermore, MHC Class II expression in osteocytes was detected in bone sampled from patients with periprosthetic joint infections, providing evidence that these mechanisms operate in vivo. Together, our findings reveal that human osteocytes are capable of inducible MHC Class II-associated antigen presentation in response to bacterial challenge, pointing to a novel role for osteocytes in adaptive immune surveillance within bone.

immunology↗

bioRxiv2023

Mitochondrial complex I as a diagnostic and therapeutic target in a mouse model of tauopathy

Dysfunction of the energy producing organelle of the cell, mitochondria, plays a pivotal role in Alzheimers disease (AD). We have recently used a novel positron emission tomographic (PET) imaging tracer targeting mitochondrial complex I (MC-I) to visualize mitochondrial abnormalities in the brains of living tau transgenic (TauTg) mice. MC-I mediates the first and limiting step in oxidative phosphorylation, the primary source of neuronal energy production. Here we used MC-I-PET to test if inhibition of mutant tau expression through transgene suppression with doxycycline could reverse mitochondrial defects in a mouse model of tauopathy and evaluate the efficacy of a MC-I-targeted candidate therapeutic, Mdivi-1. We found that late-stage suppression of mutant tau did not rescue mitochondrial deficits measured in vivo by MC-I-PET, despite reduced burden of tauopathy and neuroinflammation. These findings demonstrate that mitochondrial dysfunction may continue even if tauopathy is halted, particularly if initiated at late-stage disease. Further, we demonstrate the potential application of MC-I-PET for monitoring therapeutic efficacy, surprisingly finding detrimental effects of the mitochondrial-targeted candidate therapeutic, Mdivi-1, in TauTg mice. These findings directly contrast with the beneficial effects of Mdivi-1 observed in other models of neurodegeneration. Together, our findings highlight the need for clinical endpoints measuring mitochondrial damage in addition to markers of tauopathy in the assessment of disease prognosis and efficacy of candidate therapeutics and demonstrates the potential application of MC-I-PET to meet this need.

neuroscience↗