Itaconate promotes a wound resolving phenotype in pro-inflammatory macrophages

Maassen, Sjors; Coenen, Britt; Ioannidis, Melina; Harber, Karl J.; Grijpstra, Pieter; Bossche, Jan Van den; Bogaart, Geert van den

doi:10.1016/j.redox.2022.102591

Cited by 13 publications

(2 citation statements)

References 60 publications

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“…In addition to the expression of Mmp12, Spp1, Gpnmb, Fabp5, and Trem2, immune responsive gene 1 (Irg1) is also markedly increased in the Mmp12 hi macrophages of silicosis mice (Figure 6A). Irg1, highly expressed in activated macrophages, can mediate itaconate production in response to inflammation 27 . Ogger et al have reported the role of itaconate in controlling the severity of pulmonary fibrosis 28 .…”

Section: Resultsmentioning

confidence: 99%

Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis

Kang,

Gu,

Cao

et al. 2024

Preprint

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BackgroundSilicosis is a lethal occupational disease caused by long-term exposure to respirable silica dust. Pulmonary macrophages play a crucial role in mediating the initiation of silicosis. However, the phenotypic and functional heterogeneities of pulmonary macrophages in silicosis have not been well-studied.MethodsThe silicosis mouse model was established by intratracheal administration of silica suspension. Bronchoalveolar lavage fluids (BALFs) of mice were collected for the multiplex cytokine analysis. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were performed to reveal the heterogeneity and spatial localization of macrophages in the lung tissues. The formation of the fibrotic nodules was characterized by histology, hydroxyproline assay, and immunohistochemical staining, respectively. The expression of the pro-inflammatory or pro-fibrotic genes was investigated by quantitative polymerase chain reaction (qPCR).ResultsWe found that the level of pro-inflammatory cytokines and chemokines is significantly increased in the BALFs of silicosis mice. Apparent collagen deposition can also be observed in the silicotic lung tissues. By scRNA-seq, we have identified a subpopulation of Mmp12himacrophages significantly expanding in the lung tissues of mice with silicosis. Spatial transcriptomics analysis further confirmed that the Mmp12himacrophages are mainly enriched in silicosis nodules. Pseudotime trajectory showed that these Mmp12himacrophages, highly expressing both pro-inflammatory and pro-fibrotic genes are derived from Ly6c+monocytes. Additionally, 4-octyl itaconate (4-OI) treatment, which can alleviate pulmonary fibrosis in silicosis mice, also reduces the enrichment of the Mmp12himacrophages. Moreover, we found a subset of macrophages in BALFs derived from patients with silicosis exhibited similar characteristics of Mmp12himacrophages in silicosis mice models.ConclusionsOur study suggested that a group of Mmp12himacrophages highly express both pro-inflammatory and pro-fibrotic factors in silicosis mice, and thus may contribute to the progression of fibrosis. The findings have proposed new insights for understanding the heterogeneity of lung macrophages in silicosis, suggesting that the subset of Mmp12himacrophages may be a potential therapy target to further halt the progression of silicosis.

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Section: Resultsmentioning

confidence: 99%

Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis

Kang,

Gu,

Cao

et al. 2024

Preprint

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“…In addition, it was found that 4-OI reduced LPS-induced signaling of p38 mitogen-activated protein kinase and promoted the expression of TGF-β, while decreased the expression of collagenase matrix metalloprotease-8. Further experiments on fibrous collagen uptake of macrophage showed that 4-OI inhibited collagen uptake by activating Nrf2, possibly promoting a stronger wound-resolving phenotype [ 83 ]. Another study found that the sodium-glucose co-transporter 2 (SGLT2) inhibitor dapagliflozin could upregulate renal cortical tissue IRG1 expression and increase itaconate levels, thereby inhibiting NLRP3 inflammasome activation and protecting the kidney from ischemia–reperfusion induced fibrosis progression [ 84 ].…”

Section: Immunomodulatory Mechanisms Of Itaconatementioning

confidence: 99%

Itaconate: A Potent Macrophage Immunomodulator

Zheng

Kong

et al. 2023

Inflammation

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With advances in immunometabolic studies, more and more evidence has shown that metabolic changes profoundly affect the immune function of macrophages. The tricarboxylic acid cycle is a central metabolic pathway of cells. Itaconate, a byproduct of the tricarboxylic acid cycle, is an emerging metabolic small molecule that regulates macrophage inflammation and has received much attention for its potent anti-inflammatory effects in recent years. Itaconate regulates macrophage function through multiple mechanisms and has demonstrated promising therapeutic potential in a variety of immune and inflammatory diseases. New progress in the mechanism of itaconate continues to be made, but it also implies complexity in its action and a need for a more comprehensive understanding of its role in macrophages. In this article, we review the primary mechanisms and current research progress of itaconate in regulating macrophage immune metabolism, hoping to provide new insights and directions for future research and disease treatment.

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