Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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IL-18 Inhibition Aggravates Atherosclerosis in Jak2V617F Clonal Hematopoiesis

ABSTRACT: Clonal hematopoiesis (CH) driven by Jak2V617F is known to accelerate atherosclerosis through inflammasome activation and release of IL-1β and IL-18, yet the specific contribution of IL-18 has remained unclear. In this study, we demonstrate that antibody inhibition of IL-18 in Jak2V617F CH mice increases plaque collagen but paradoxically promotes both early lesion growth and advanced necrotic core formation. Mechanistically, IL-18 blockade reverses AIM2 inflammasome activation but shifts cell death toward apoptosis, and together with impaired efferocytosis, results in greater necrosis. These events appear to be coordinated by reduced IFN-γ signaling, which enhanced collagen deposition while decreasing expression of efferocytotic genes.Our findings challenge the prevailing notion that IL-18 inhibition stabilizes atherosclerotic plaques in CH and provide new mechanistic insight into the interplay between inflammasome biology, adaptive immunity, and plaque stability.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Cheng-Chieh Hsu

PROVIDER: E-MTAB-15736 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Somatic mutations that cause the clonal outgrowth of mutant hematopoietic stem cells (HSCs), known as clonal hematopoiesis (CH), decay myeloid heterogeneity, activate inflammation, and increase the risk of atherosclerosis. However, whether lifestyle alters myeloid cell diversity by either modulating CH clone expansion or the phenotypic programming of CH mutant cells, thereby impacting atherosclerosis, is unknown. Here, in humans and mice and across mutations in Jak2, Tet2, p53 and Dnmt3a, we demonstrate mutation-dependent responses to lifestyle in CH and show that mutant cells are uniquely and selectively sensitive to lifestyle exposures. Sleep and exercise restrict Jak2 and Tet2 CH and its atherogenic consequences by diminishing the clonal expansion of mutant HSCs and reprogramming mutant bone marrow (BM) HSCs and aortic macrophages, but not their neighboring wildtype (WT) counterparts, through divergent brain-body axes. In two large human datasets, moderate-to-vigorous physical associated with less non-DNMT3A CH. In atherogenic mice with Jak2 or Tet2 but not p53 or Dnmt3a CH, uninterrupted sleep or exercise curtails clone expansion. In Jak2 CH sleep and exercise do so by selectively reprogramming mutant, but not WT, BM HSCs towards anti-proliferative and metabolically healthy phenotypes by tempering BM macrophage-HSC IL-1β signaling. Sleep or exercise also lessens Jak2-, Tet2-, and p53-, but not Dnmt3a-, driven atherosclerosis, partly independent of BM clonal dynamics, by locally reprogramming mutant macrophages in atherosclerotic lesions. In Jak2 mutant, but not adjacent WT, aortic macrophages, uninterrupted sleep reduces cell death, selectively blunting CLEC4E-dependent inflammasome activation and IL-1β generation, consequently diminishing lesions. Exercise, meanwhile, activates PAC1+ neurons in the brain’s locus coeruleus (LC), raising peripheral norepinephrine (NE), and preserves the expression of NE’s adrenergic receptor (ADR) β2 in Jak2V617F, but not cohabitant WT, aortic macrophages. Exercise-mediated NE signaling from the brain’s LC to Jak2V617F aortic macrophages selectively represses their inflammatory programing and atherosclerosis. Together, our findings uncover gene-lifestyle coaction and establish that healthy lifestyles gene-specifically diminish CH and selectively reprogram mutant HSCs and macrophages to maintain myeloid heterogeneity and cardiovascular health.

Project description:Microglia and neuroinflammation are implicated in the development and progression of Alzheimer’s disease (AD). To better understand microglia-mediated processes in AD, we studied the function of INPP5D/SHIP1, a gene linked to AD through GWAS. Immunostaining and single nucleus RNA sequencing confirmed that INPP5D expression in the adult human brain is enriched in microglia. Examination of prefrontal cortex across a large cohort revealed reduced full-length soluble INPP5D protein levels in AD patient brains compared to cognitively normal controls. However, elevated INPP5D immunostaining in microglia in the AD brain was observed, which was driven by elevations in plaque-associated microglia suggesting that these two methods quantify different pools of INPP5D. Examination of INPP5D overexpression and bi-allelic loss-of-function in induced pluripotent stem cell derived microglia (iMGs) revealed that INPP5D LOF most closely resemble microglia in the AD brain with respect to immune signaling alterations, supporting the hypothesis that INPP5D function is reduced in AD microglia. The functional consequences of reduced INPP5D activity were evaluated in human iMGs, using both pharmacological inhibition of the phosphatase activity of INPP5D and genetic reduction in copy number. Unbiased transcriptional and proteomic profiling of these iMGs suggested an upregulation of innate immune signaling pathways, lower levels of scavenger receptors, reduced lysosomal proteins and altered inflammasome signaling with INPP5D reduction. INPP5D inhibition induced the secretion of IL-1ß and IL-18, further implicating inflammasome activation. Inflammasome activation was confirmed through visualization of inflammasome formation through ASC immunostaining in INPP5D-inhibited iMGs, increased cleaved caspase-1 and through rescue of elevated IL-1ß and IL-18 with caspase-1 and NLRP3 inhibitors. In accord, lower INPP5D is associated with higher IL-18 levels and an elevation in microglia with ASC specks in the AD brain. This work implicates INPP5D as a regulator of inflammasome signaling in human microglia.

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IL-18 Inhibition Aggravates Atherosclerosis in Jak2V617F Clonal Hematopoiesis

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