Biology subjects

Ainsworth, R.

Publications and source records attributed to Ainsworth, R..

3 recordsLinked to original sources

bioRxiv2025

Mitochondrial instability contributes to IFN-driven heart disease.

AimsType I interferons (IFNs) are linked to an increased risk of cardiovascular disease and are chronically elevated in systemic autoimmune diseases such as systemic lupus erythematosus (SLE). We evaluated the effect of chronic IFNa exposure on cardiac and cardiomyocyte function in order to better understand IFN-driven cardiac disease from the perspective of SLE. Methods and ResultsAdministration of the TLR7/8 agonist, resiquimod, to C57BL6 mice, drove chronic IFN induction and reduced ejection fraction and fractional shortening compared to mice treated with vehicle control. Multiomic analysis demonstrated increased IFN signature in resiquimod treated hearts (transcriptomic and proteomic) and a decrease in genes and proteins representing electron transport chain (ETC) and cytochrome complex assembly. Integration of metabolomics with transcriptomics revealed pathways representing chemokine signaling, Toll-like receptor signaling, HIF-1 signaling and Dilated cardiomyopathy. As our in vivo model of IFN-driven SLE-like heart disease showed both proteomic and transcriptomic changes that reflected changes in mitochondrial and potentially cardiac function, we conducted an in vitro analysis of the effects of acute and chronic IFN on cardiomyocytes, the most energetically demanding cell type in the heart, and the cells most susceptible to stress and inflammation. As with our in vivo findings, proteomic and transcriptomic analysis of AC16 cardiomyocytes exposed to chronic IFN indicated perturbation of mitochondrial pathways. Extracellular flux analysis of chronically exposed AC16 cells showed impaired basal respiration, maximal respiration, ATP production and non-glycolytic acidification, glycolysis and glycolytic capacity, indicating increased mitochondrial stress in response to chronic exposure to IFNa. MitoTracker green staining showed increased fragmentation and perinuclear localization in AC16 chronically exposed to IFN and an increase in mtDNA release and expression of proteins known to contribute to mtDNA release and detection. ConclusionsOur results directly support a role for chronic IFN in driving cardiac dysfunction in both a mouse model of IFN-driven disease that mimics SLE and in cardiomyocytes, though enhanced mitochondrial stress, mtDNA release and potentially exacerbation of cGAS-STING-IFN axis. Translational PerspectivesMany immune features of SLE such as elevated type I interferons, chronic inflammation, and persistent autoantibody production are strongly correlated with increased cardiovascular risk, but it remains difficult to prove direct biological causation. This study demonstrates that chronic IFN exposure induces mitochondrial dysfunction and mtDNA release in cardiomyocytes, directly complementing an in vivo model of SLE-cardiac disease. It suggests that targeting IFNs may reduce CVD risk in IFN-driven autoimmunity.

immunology↗

bioRxiv2025

A CD57+ cytotoxic CD8 T cell subset associated with fibrotic lung disease in systemic sclerosis

Interstitial lung disease (ILD) is a major cause of morbidity and mortality in systemic sclerosis (SSc); however, the immunopathologic mechanisms driving lung disease in SSc are unclear. T cells have been implicated as a likely driver of lung injury in SSc. Here, we have evaluated T cells in blood and lungs of patients with SSc-ILD and identified a specific population of cytotoxic CD8 T cells that is expanded in SSc-ILD patients. Cytotoxic effector memory CD8 T cells marked by CD57 expression are preferentially expanded in SSc-ILD patients compared to SSc patients without ILD and controls and show prominent clonal expansion. These CD57+ T effector memory (TEM) cells differ from T effector memory cells re-expressing CD45RA (TEMRA) transcriptomically and functionally, with cytotoxic function that is enhanced by CD155 engagement of the costimulatory receptor CD226. Analyses of cells from ILD lungs indicate endothelial cells as a likely source of CD155 to activate CD57+ cytotoxic T cells. Together, the results implicate a CD57+ cytotoxic CD8 T cell population as a potential mediator of lung injury in SSc-ILD.

immunology↗

bioRxiv2019

Eosinophil deficiency promotes aberrant repair and adverse remodelling following acute myocardial infarction

BackgroundEosinophil count predicts outcome following myocardial infarction (MI) and eosinophils regulate tissue repair and regeneration in extra-cardiac settings.\n\nObjectivesTo investigate the role of eosinophils in regulating inflammation, repair and remodelling following MI.\n\nMethodsBlood eosinophil count was assessed in 732 patients undergoing primary percutaneous coronary intervention for ST-segment elevation MI (STEMI). Experimental MI was induced in wild-type (WT) and eosinophil-depleted mice ({Delta}dblGATA or anti-Siglec F antibody treated). Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of infarct digests.\n\nResultsBlood eosinophil count declined in the hours following STEMI in patients and following MI induction in mice. Eosinophils were subsequently identified in the myocardium of patients and mice. Genetic eosinophil depletion in mice increased LV dilatation (end-systolic area: 29.0{+/-}2.2cm2 v 21.6{+/-}1.6cm2; p=0.02) and reduced ejection fraction (22.0{+/-}3.6% v 34.3{+/-}4.0% in p=0.04,) in {Delta}dblGATA v WT following MI (n=8-9/group), an outcome reproduced by pharmacological depletion. {Delta}dblGATA mice had increased scar size with disrupted collagen deposition and altered expression of the collagen cross-linking genes plod2 and lox. CD206+pro-repair macrophages were less prevalent in the infarct zone of {Delta}dblGATA mice (27.0{+/-}2.3% v WT: 39.2.4{+/-}3.5%; p=0.01, n=9-11/group) but were restored by replenishment with bone marrow-derived eosinophils. Anti-inflammatory cytokine concentrations were reduced in {Delta}dblGATA mice and IL-4 complex administration 24h after MI rescued adverse remodelling.\n\nConclusionsEosinophils are recruited to the heart following MI and are required for effective repair and to prevent adverse remodelling. IL-4 therapy has potential to limit detrimental outcomes when eosinophil availability is low.\n\nHIGHLIGHTSA drop in eosinophil blood count is associated with recruitment of eosinophils to the heart during repair following clinical and experimental myocardial infarction.\n\nGenetic & pharmacological eosinophil depletion leads to increased adverse remodelling in experimental MI.\n\nEosinophils are required for aquisition of an anti-inflammatory macrophage phenotype and a shift to resolution of inflammation during infarct repair.\n\nInterleukin-4 therapy is able to rescue the adverse remodelling phenotype in conditions of eosinophil deficiency.\n\nCondensed abstractIn ST-segment elevation myocardial infarction (STEMI) of both patients and mice, there was a decline in blood eosinophil count, with activated eosinophils recruited to the infarct zone. Eosinophil deficiency resulted in attenuated anti-inflammatory pro-repair macrophage polarization, enhanced myocardial inflammation, increased scar size and deterioration of myocardial structure and function. Adverse cardiac remodelling in the setting of eosinophil deficiency was prevented by IL-4 therapy.

immunology↗