Expression of Chitotriosidase in Macrophages Modulates Atherosclerotic Plaque Formation in Hyperlipidemic Mice

Abstract

Objective: To determine whether overexpression of the chitin degrading enzyme, chitotriosidase (CHIT1), modulates macrophage function and ameliorates atherosclerosis. Approach and Results: Using a mouse model that conditionally overexpresses CHIT1 in macrophages (CHIT1-Tg) crossbred with the Ldlr −/− mouse provided us with a means to investigate the effects of CHIT1 overexpression in the context of atherosclerosis. In vitro, CHIT1 overexpression by murine macrophages enhanced protein expression of IL-4, IL-8, and G-CSF by BMDM upon stimulation with a combination of lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Phosphorylation of ERK1/2 and Akt was also down regulated when exposed to the same inflammatory stimuli. Hyperlipidemic, Ldlr −/−-CHIT1-Tg (CHIT1-OE) mice were fed a high-fat diet for 12 weeks in order to study CHIT1 overexpression in atherosclerosis. Although plaque size and lesion area were not affected by CHIT1 overexpression in vivo, the content of hyaluronic acid (HA) and collagen within atherosclerotic plaques of CHIT1-OE mice was significantly greater. Localization of both ECM components was markedly different between groups. Conclusions: These data demonstrate that CHIT1 alters cytokine expression and signaling pathways of classically activated macrophages. In vivo, CHIT1 modifies ECM distribution and content in atherosclerotic plaques, both of which are important therapeutic targets.

Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control

“…Group 3 (shown in blue) was significantly more abundant in low-bacterial-burden granulomas (p = 0.026; Figure 6 B; Table S5 ) and consisted of many T cell subclusters/subpopulations, including stem-like; cytotoxic subclusters C2, C4, and C6; metallothionein; proliferating; SRRM2+; and T1-T17 subpopulations 1, 3, and 4, as well as Mac7. This macrophage subset was distinguished in part, by expression of the immunomodulatory genes IDO and CHIT (encoding chitotriosidase), which is abundantly produced by lipid-laden macrophages in other conditions such as Gaucher’s disease, Niemenn-Pick disease, and atherosclerosis ( Barone et al., 2007 ; Yap et al., 2020 ).

Figure 6 Cellular ecosystem in TB lung granulomas (A) Pairwise Pearson correlation values of cell type proportions across 26 10-week p.i.

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Trehalose Activates Hepatic and Myocardial Autophagy and Has Anti-Inflammatory Effects in db/db Diabetic Mice

“…CHIA is expressed in epithelial cells and certain immune cells, such as neutrophils and macrophages in various organs of mice [ 55 , 56 ]. Human Kupffer cells are reported to oversecrete CHIT1 in steatohepatitis, and this phenomenon can be attributed to some complication of steatohepatitis [ 57 , 58 , 59 ]. By contrast, normal functions of CHIT1 have not been studied sufficiently until now [ 42 ].…”

Leishmania kinetoplast DNA contributes to parasite burden in infected macrophages: Critical role of the cGAS-STING-TBK1 signaling pathway in macrophage parasitemia

“…Among the shared up-regulated genes, SLAMF7 stands out as a receptor linked to superactivated macrophage phenotype ( 51 ). Similarly, granulysin and chitotriosidase expression in macrophages were associated with microbial defense ( 52 , 53 ). Among the downregulated genes, ITGA5 (integrin subunit alpha 5) stands out since the protein encoded by this gene is a constituent of fibronectin receptor (integrin α5β1) which has a prominent role in promastigote internalization ( 54 ).…”