Biology subjects

Neal, J.

Publications and source records attributed to Neal, J..

3 recordsLinked to original sources

bioRxiv2024

A Novel Therapeutic Approach using CXCR3 Blockade to Treat Immune Checkpoint Inhibitor-mediated Myocarditis

BackgroundImmune checkpoint inhibitors (ICIs) are successful in treating many cancers but may cause immune-related adverse events. ICI-mediated myocarditis has a high fatality rate of up to 40%, with severe cardiovascular consequences. Targeted therapies for ICI myocarditis are currently lacking. MethodsWe used a genetic mouse model of PD-1 deletion (MRL/Pdcd1-/-) along with a novel drug-treated ICI myocarditis mouse model to recapitulate the disease phenotype. We performed single-cell RNA-sequencing (scRNAseq), single-cell T-cell receptor sequencing (scTCR-seq), and cellular indexing of transcriptomes and epitopes (CITE-seq) on immune cells isolated from MRL and MRL/Pdcd1-/- mice at serial timepoints. We assessed the impact of macrophage deletion in MRL/Pdcd1-/- mice, then inhibited CXC chemokine receptor 3 (CXCR3) in ICI-treated mice to assess therapeutic effect on myocarditis phenotype. Furthermore, we delineated functional effects of CXCR3 blockade on T-cell and macrophage interactions in a transwell assay. We then correlated the results in human single-cell multi-omics data from blood and heart biopsy data from patients with ICI myocarditis. ResultsSingle-cell multi-omics demonstrated expansion of CXCL9/10+CCR2+ macrophages and CXCR3hi CD8+ effector T-lymphocytes in the hearts of MRL/Pdcd1-/- mice correlating with onset of myocarditis development. Both depletion of CXCL9/10+CCR2+ macrophages and CXCR3 blockade respectively led to decreased CXCR3hiCD8+ T-cell infiltration into the heart and significantly improved survival. A transwell assay showed that selective blockade of CXCR3 and its ligand, CXCL10 decreased CD8+ T-cell migration towards macrophages, implicating this interaction in T-cell cardiotropism towards cardiac macrophages. Cardiac biopsies from patients with confirmed ICI myocarditis demonstrated infiltrating CXCR3+ lymphocytes and CXCL9+/CXCL10+ macrophages. Both mouse cardiac immune cells and patient peripheral blood immune cells revealed expanded TCRs correlating with CXCR3hi CD8+ T-cells in ICI myocarditis samples. ConclusionsThese findings bring forth the CXCR3-CXCL9/10 axis as an attractive therapeutic target for ICI myocarditis treatment, and more broadly, as a druggable pathway in cardiac inflammation.

cell biology↗

bioRxiv2022

Association of intrinsic functional connectivity between the locus coeruleus and salience network with attentional ability

The LC is a brainstem region associated with broad physiological and neural arousal as part of the release of norepinephrine, but it has increasingly been associated with multiple specific cognitive processes. These include sustained attention, deficits in which are associated with a variety of neuropsychological disorders. Neural models of attention deficits to date have focused on interrupted dynamics between the salience network (SAL) with the fronto-parietal network (FPN), which has been associated with task-switching and processing of external stimuli, respectively. Conflicting findings based on these regions suggest the possibility of upstream signaling leading to attention dysfunction, and recent research suggest the LC may play this role. In this study, resting-state functional connectivity (FC) and behavioral performance on an attention task was examined within 584 individuals. Analysis revealed significant clusters connected to the LC activity in the bilateral insula, anterior cingulate cortex (ACC), and bilateral ventral striatum, all regions associated with the SAL. Given previous findings that attention deficits may be caused by dysfunctions in network switching by the SAL, our findings here further suggest that dysfunction in LC signaling to the SAL may interfere with attention.

neuroscience↗

bioRxiv2021

Age-related intrinsic functional connectivity changes of locus coeruleus from childhood to older adults

The locus coeruleus is critical for selective information processing by modulating brains connectivity configuration. Increasingly studies have suggested that LC controls sensory inputs at the sensory gating stage. Furthermore, accumulating evidence has examined that young children and older adults are more prone to distraction and filter out irrelevant information less efficiently, possibly due to the impaired LC connectivity. However, the LC connectivity pattern across the life span is not fully examined yet, hampering our ability to understand the relationship between LC development and the distractibility. In this study, we examined the intrinsic network connectivity of the LC using resting-state fMRI from the enhanced NKI dataset with wide-range age samples. Based on LC-seed functional connectivity maps, we examined the age-related variation in the LC connectivity with a quadratic model. The analyses revealed two connectivity patterns explicitly. The sensory-related brain regions showed a positive quadratic age effect (u-shape), and the frontal regions for the cognitive control showed a negative quadratic age effect (inverted u-shape). Our results imply that such age-related distractibility is possibly due to the impaired sensory gating by the LC and the insufficient top-down controls by the frontal regions. We discuss the underlying neural mechanisms and limitations of our study.

neuroscience↗