Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice
Wenli Liu, … , Nan Wang, Alan R. Tall
Wenli Liu, … , Nan Wang, Alan R. Tall
Published November 12, 2024
Citation Information: J Clin Invest. 2025;135(1):e182939. https://doi.org/10.1172/JCI182939.
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Inflammatory crosstalk impairs phagocytic receptors and aggravates atherosclerosis in clonal hematopoiesis in mice

Abstract

Clonal hematopoiesis (CH) increases inflammasome-linked atherosclerosis, but the mechanisms by which CH mutant cells transmit inflammatory signals to nonmutant cells are largely unknown. To address this question, we transplanted 1.5% Jak2V617F (Jak2VF) bone marrow (BM) cells with 98.5% WT BM cells into hyperlipidemic Ldlr–/– mice. Low-allele-burden (LAB) mice showed accelerated atherosclerosis with increased features of plaque instability, decreased levels of the macrophage phagocytic receptors c-Mer tyrosine kinase (MERTK) and triggering receptor expressed on myeloid cells 2 (TREM2), and increased neutrophil extracellular traps (NETs). These changes were reversed when Jak2VF BM was transplanted with Il1r1–/– BM. LAB mice with noncleavable MERTK in WT BM showed improvements in necrotic core and fibrous cap formation and reduced NETs. An agonistic TREM2 antibody (4D9) markedly increased fibrous caps in both control and LAB mice, eliminating the difference between the groups. Mechanistically, 4D9 increased TREM2+PDGFB+ macrophages and PDGF receptor-α+ fibroblast–like cells in the cap region. TREM2 and PDGFB mRNA levels were positively correlated in human carotid plaques and coexpressed in macrophages. In summary, low frequencies of Jak2VF mutations promoted atherosclerosis via IL-1 signaling from Jak2VF to WT macrophages and neutrophils, promoting cleavage of phagocytic receptors and features of plaque instability. Therapeutic approaches that stabilize MERTK or TREM2 could promote plaque stabilization, especially in CH- and inflammasome-driven atherosclerosis.

Authors

Wenli Liu, Brian D. Hardaway, Eunyoung Kim, Jessica Pauli, Justus Leonard Wettich, Mustafa Yalcinkaya, Cheng-Chieh Hsu, Tong Xiao, Muredach P. Reilly, Ira Tabas, Lars Maegdefessel, Kai Schlepckow, Christian Haass, Nan Wang, Alan R. Tall

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Figure 1

Accelerated atherogenesis and plaque instability in LAB Jak2VF CH mice.

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Accelerated atherogenesis and plaque instability in LAB Jak2VF CH mice. ...
(A) Experimental design. (B) Plasma cholesterol (CHO) levels. (C) Representative H&E staining and quantification of the lesion and necrotic core areas in aortic root sections. Necrotic core regions are indicated by dotted lines. Scale bar: 200 μm. Original magnification, ×100. (D) Aortic root sections were stained with Masson’s trichrome for the fibrous cap (outlined by dashed lines) and collagen content area and then quantified as the ratio of the total lesion area. Scale bar: 100 μm. (E and F) Representative immunofluorescence staining of macrophages (anti-Mac2) and GFP and quantification of the absolute Mac2+ area, the GFP–Mac2+ (Mx1-Cre or Jak2VF macrophages) area, and the GFP+Mac2+ area (WT macrophages), as well as the GFP–Mac2+ area as the percentage of the total Mac2+ area in aortic root sections. Scale bar: 250 μm. Original magnification, ×50. (G) Representative immunofluorescence staining for H3cit and MPO and quantification of the double-positive area (NETosis) as a percentage of the lesion area. Scale bar: 200 μm. Original magnification, ×200. (H) Representative immunofluorescence staining for IL-1β and anti-Mac2 (macrophages) and quantification of the fluorescence intensity of IL-1β were performed and normalized to the lesion area. Scale bar: 50 μm. Original magnification, ×100. Data are presented as the mean ± SEM. n = 15 (B–G), n = 13 (H). *P < 0.05 and **P < 0.01, by unpaired, 2-tailed Student’s t test.