Inflammatory crosstalk between macrophages and stromal cells in clonal hematopoiesis

  • Tall, A. R. (PI)

Project: Research project

Project Details

Description

Clonal hematopoiesis (CH) arises from somatic mutations such as in JAK2 or TET2 that provide a fitness advantage to hematopoietic stem cells and outgrowth of clones of blood cells. CH, which increases in frequency with aging, has emerged as a major independent risk factor for CVD. Studies in Tet2-/- and Jak2VF mouse models indicate a central role of macrophage inflammasome activation. In collaboration with Drs Tabas and Reilly, we have shown increased atherosclerosis, defective efferocytosis, increased necrosis and inflammatory myeloid cell populations in mice expressing Jak2VF in hematopoietic cells. Inhibition of the inflammasome product lL-1β improved features of plaques stabilization including increased fibrous caps and decreased necrotic cores. The overall hypothesis is that in several forms of CH including Jak2VF and Tet2, inflammasome activation and IL-1 release from mutant cells promote adverse changes in WT Μφs and stromal cells to induce plaque destabilization. These studies will synergize with those proposed by Drs Tabas and Zhang that are probing the mechanisms of defective efferocytosis and thinning of lesional fibrous caps which are key features of atherosclerotic plaque vulnerability and the major PPG theme. In Aim 1 we will assess the impact of Jak2VF-CH on bystander cells in lesions focusing on CH Μφ - WT Μφ crosstalk. We will use scRNAseq to evaluate the hypothesis that IL-1 secretion from Jak2VF Μφs reduces efferocytic Trem2Hi Μφs and increases inflammatory Μφs. We will employ novel Trem2 stabilizing antibodies to block Trem2 cleavage by IL-1, introduce a transgenic non-cleavable form of MerTK developed by Dr Tabas and in collaboration with Dr Zhang introduce deficiency of Pdcd6ip a novel negative regulator of efferocytosis, to see if these potential therapeutic approaches improve efferocytosis, necrotic core and fibrous cap formation. In Aim 2 we will assess the impact of Jak2VF- and Tet2-/-- CH on Μφ-fibroblast crosstalk. scRNAseq and SMC fate mapping with Dr Reilly shows that IL-1β inhibition in Jak2VF and Tet2 CH mice increases non-SMC-derived fibroblasts in fibrous caps. We will use fate mapping studies to assess the hypothesis that fibroblasts are derived from mesenchymal stem cells (MSCs). Aim 3 will involve translational studies in human carotid plaques. We will collaborate with Dr Maegdefessel, Tabas, Zhang and the Munich Vascular Biobank to test the hypothesis that CH mutations in TET2, JAK2 and DNMT3A are associated with increased inflammatory Μφs and decreased Trem2Hi Μφs in carotid plaques with adverse impact on features of plaque stability. Cells expressing inflammatory or pro-resolving genes will be visualized at single cell resolution in advanced vs early plaques and in unstable vs stable plaques. These collaborative studies may reveal novel genes and pathways acting downstream of inflammasome activation in clonal hematopoiesis to destabilize plaques and point to new and more precisely targeted therapeutic approaches that are less immunosuppressive than global inhibition of IL-1β or inflammasomes.
StatusActive
Effective start/end date7/1/245/31/25

ASJC Scopus Subject Areas

  • Biotechnology

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