Biology subjects

Demehri, S.

Publications and source records attributed to Demehri, S..

3 recordsLinked to original sources

bioRxiv2023

Cytotoxic CD4+ T cells eliminate senescent cells by targeting cytomegalovirus antigen

Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old compared with young skin. However, they did not increase with advancing age in the elderly. Increased CXCL9 and cytotoxic CD4+ T cell (CD4 CTL) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTL eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTL from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which can be directly eliminated by CD4 CTL through the recognition of the HCMV-gB antigen.

immunology↗

bioRxiv2022

Senescent Preosteoclast Secretome Promotes Metabolic Syndrome Associated Osteoarthritis through Cyclooxygenase 2

BackgroundMetabolic syndrome-associated osteoarthritis (MetS-OA) is a distinct osteoarthritis phenotype defined by the coexistence of MetS or its individual components. Despite the high prevalence of MetS-OA, its pathogenic mechanisms are unclear. The aim of this study was to determine the role of cellular senescence in the development of MetS-OA. MethodsAnalysis of the human osteoarthritis initiative (OAI) dataset was conducted to investigate the MRI subchondral bone features of MetS-human OA participants. Joint phenotype and senescent cells were evaluated in two MetS-OA mouse models: high-fat diet (HFD)-challenged mice and STR/Ort mice. In addition, the molecular mechanisms by which preosteoclasts become senescent as well as how the senescent preosteoclasts impair subchondral bone microenvironment were characterized using in vitro preosteoclast culture system. ResultsHumans and mice with MetS are more likely to develop osteoarthritis-related subchondral bone alterations than those without MetS. MetS-OA mice exhibited a rapid increase in joint subchondral bone plate and trabecular thickness before articular cartilage degeneration. Subchondral preosteoclasts undergo senescence at the pre- or early-osteoarthritis stage and acquire a unique secretome to stimulate osteoblast differentiation and inhibit osteoclast differentiation. Antagonizing preosteoclast senescence markedly mitigates pathological subchondral alterations and osteoarthritis progression in MetS-OA mice. At the molecular level, preosteoclast secretome activates COX2-PGE2, resulting in stimulated differentiation of osteoblast progenitors for subchondral bone formation. Administration of a selective COX2 inhibitor attenuated subchondral bone alteration and osteoarthritis progression in MetS-OA mice. Longitudinal analyses of the human Osteoarthritis Initiative (OAI) cohort dataset also revealed that COX2 inhibitor use, relative to non-selective nonsteroidal anti-inflammatory drug use, is associated with less progression of osteoarthritis and subchondral bone marrow lesion worsening in participants with MetS-OA. ConclusionsOur findings suggest a central role of a senescent preosteoclast secretome-COX2/PGE2 axis in the pathogenesis of MetS-OA, in which selective COX2 inhibitors may have disease-modifying potential. FundingThis work was supported by the National Institutes of Health grant R01AG068226 and R01AG072090 to M.W., R01AR079620 to S.D., and P01AG066603 to X.C.

cell biology↗

bioRxiv2021

Fractional Laser Treatment Boosts Systemic Anti-Tumor Immunity in Combination with OX40 Agonist and PD-1 Blockade

While ablative fractional photothermolysis (aFP) with a 10,600 nm CO2 laser is employed for a wide variety of dermatologic conditions, its applications in oncology are relatively unexplored. Building off our previous work, we investigated the effect of unilateral aFP treatment in combination with anti-PD-1 blocking antibody and OX40 agonist on bilateral tumor growth and remission. A CT26 wild type (CT26WT) colon carcinoma cell line was established bilaterally on the hind flanks of a standardized mouse model and tumor characteristics were investigated on aFP treated and untreated sides. Remarkably, triple therapy with fractional CO2 laser in combination with anti-PD-1 antibodies and OX40 agonists resulted in significantly slower tumor growth and complete remissions on bilateral tumors. Flow cytometric analysis showed the triple treatments elicited an increase of granzyme B+ CD8+T cells due to synergistic effect of aFP treatment and the checkpoint molecules, including the induction of CD103+ CCR7+ dendritic cells (DCs) in aFP-treated tumor by aFP treatment, XCR1+ DCs in drainage lymph node by anti-PD-1 inhibitor and OX40+ Ki67+ CD8+ T cells in the lymph node by OX40 agonist. Triple therapy-mediated tumor regression and survival was abrogated upon CD8+ T cell depletion. Importantly, when two mismatched cancer cells were implanted into mice, the effect of the triple therapy on distant tumor was abrogated, showing antigen specificity of the T cell immunity induced by triple therapy. This study highlights the efficacy of aFP a novel adjuvant for current cancer immunotherapeutics.

immunology↗