Biology subjects

English, K.

Publications and source records attributed to English, K..

4 recordsLinked to original sources

bioRxiv2025

The PPARβ/δ-induced mesenchymal stromal cell secretome has cytoprotective effects via ANGPTL4 in a pre-clinical model of acute lung inflammation

RationaleHuman bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are known to exert immunomodulatory and pro-reparative effects in vivo. This makes hBM-MSCs an enticing therapeutic candidate for inflammatory diseases, such as acute respiratory distress syndrome (ARDS). The ARDS microenvironment is complex and contains an abundance of free fatty acids (FFAs); which are known to differentially impact MSC functionality. PPAR{beta}/{delta} is a ubiquitously expressed nuclear receptor that is activated in response to FFA-binding. PPAR{beta}/{delta} has been shown to impact the therapeutic efficacy of mouse MSCs. ObjectiveThis study sought to investigate the impact of PPAR{beta}/{delta}-modulation on human MSC functionality in vitro and in vivo. MethodshBM-MSCs were exposed to a synthetic PPAR{beta}/{delta} agonist/antagonist in the presence or absence of ARDS patient serum and the immunomodulatory and pro-reparative capacity of the MSC secretome was investigated using in vitro assays and a pre-clinical model of LPS-induced acute lung inflammation (ALI). ResultsOur results highlighted enhanced pro-reparative capacity of PPAR{beta}/{delta}-agonised hBM-MSCs secretome in CALU-3 lung epithelial cells, mediated by MSC derived angiopoietin-like 4 (ANGPTL4). PPAR{beta}/{delta}-induced ANGPTL4-high MSC secretome facilitated enhanced endothelial barrier integrity in the lungs of ALI mice. Therapeutic effects of PPAR{beta}/{delta}-agonised hBM-MSCs secretome were further enhanced by licensing MSCs with human ARDS patient serum. ARDS-licensed PPAR{beta}/{delta}-induced ANGPTL4-high MSC secretome had reduced clinical score and weight loss. The role ANGPL4 in these protective effects was confirmed using an anti-ANGPTL4 antibody. ConclusionThese findings conclude that the MSC secretome therapeutic effects can be enhanced both in vitro and in vivo through licensing strategies that upregulate the angiogenic factor ANGPTL4. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/667170v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@a03b3dorg.highwire.dtl.DTLVardef@1915253org.highwire.dtl.DTLVardef@1b3fd4aorg.highwire.dtl.DTLVardef@1ba27ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2022

Mucosal associated invariant T cells are altered in patients with Hidradenitis Suppurativa and contribute to the inflammatory milieu

Mucosal Associated Invariant T cells are a population of "innate" T cells, which express the invariant T cell receptor (TCR) chain V 7.2-J 33 and are capable of robust rapid cytokine secretion, producing a milieu of cytokines including IFN-{gamma} and IL-17. MAIT cells have been reported in multiple human tissues including the gut, periphery and skin. On-going research has highlighted their involvement in numerous inflammatory diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is currently unknown. In this study we show for the first time, that MAIT cells are altered in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17 cytokine bias. We show that CCL20 expression is elevated in lesions of patients with H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT cells can accumulate in the lesions from patients with H.S. when compared to adjacent skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation of dermal fibroblasts, promoting the expression of chemotactic signals including CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively our data details IL-17 producing MAIT cells as a novel player in the pathogenesis of H.S and highlights the potential of RORyt inhibition as a novel therapeutic strategy.

immunology↗

bioRxiv2020

The self-peptide repertoire plays a critical role in transplant tolerance induction

While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically-engineered MHC class I (MHC I) constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify a high proportion of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large component of the alloresponse.

immunology↗

bioRxiv2019

Astrocytes improve neuronal health after cisplatin treatment through mitochondrial transfer.

Neurodegenerative disorders, including chemotherapy-induced cognitive impairment, are associated with neuronal mitochondrial dysfunction. Cisplatin, a commonly used chemotherapeutic, induces neuronal mitochondrial dysfunction in vivo and in vitro. Astrocytes are key players in supporting neuronal development, synaptogenesis, axonal growth, metabolism and, potentially, mitochondrial health. We tested the hypothesis that astrocytes transfer healthy mitochondria to neurons after cisplatin treatment to restore neuronal health. We used an in vitro system in which astrocytes containing mito-mCherry-labeled mitochondria were co-cultured with primary cortical neurons damaged by cisplatin. Culture of primary cortical neurons with cisplatin reduced neuronal survival and depolarized neuronal mitochondrial membrane potential. Cisplatin induced abnormalities in neuronal calcium dynamics characterized by increased resting calcium levels, reduced calcium responses to stimulation with KCl, and slower calcium clearance. The same dose of cisplatin that caused neuronal damage did not affect astrocyte survival or astrocytic mitochondrial respiration. Co-culture of cisplatin-treated neurons with astrocytes increased neuronal survival, restored neuronal mitochondrial membrane potential, and normalized neuronal calcium dynamics especially in those neurons that had received mitochondria from astrocytes. These beneficial effects of astrocytes were associated with transfer of mitochondria from astrocytes to cisplatin-treated neurons. The Rho-GTPase Miro-1 is known to contribute to mitochondrial motility and transfer. We show that siRNA-mediated knockdown of Miro-1 in astrocytes reduced mitochondrial transfer from astrocytes to neurons and prevented the normalization of neuronal calcium dynamics. In conclusion, we identified transfer of mitochondria from astrocytes to neurons damaged by cisplatin as an important repair mechanism to protect cortical neurons against the toxic effects of this chemotherapeutic. Significance statementChemotherapy-induced neurotoxicity is a serious health problem and little is known about the underlying mechanisms. Especially neurons are very sensitive to cisplatin treatment. We show that astrocytes can protect neurons damaged by cisplatin by improving neuronal survival, mitochondrial health, and calcium dynamics in vitro. This beneficial effect of astrocytes is dependent on the transfer of mitochondria from astrocytes to the damaged neurons. Our findings provide evidence for an important endogenous protective neuro-glial mechanism that could contribute to prevention of neuronal death as a result of cisplatin treatment and thereby aid in sustaining brain health of patients during chemotherapy.

neuroscience↗