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- Title
Regulation of macrophage polarization by targeted metabolic reprogramming for the treatment of lupus nephritis.
- Authors
Zhao, Limei; Tang, Shuqin; Chen, Fahui; Ren, Xiya; Han, Xiutao; Zhou, Xiaoshuang
- Abstract
Lupus nephritis (LN) is a severe and common manifestation of systemic lupus erythematosus (SLE) that is frequently identified with a poor prognosis. Macrophages play an important role in its pathogenesis. Different macrophage subtypes have different effects on lupus-affected kidneys. Based on their origin, macrophages can be divided into monocyte-derived macrophages (MoMacs) and tissue-resident macrophages (TrMacs). During nephritis, TrMacs develop a hybrid pro-inflammatory and anti-inflammatory functional phenotype, as they do not secrete arginase or nitric oxide (NO) when stimulated by cytokines. The infiltration of these mixed-phenotype macrophages is related to the continuous damage caused by immune complexes and exposure to circulating inflammatory mediators, which is an indication of the failure to resolve inflammation. On the other hand, MoMacs differentiate into M1 or M2 cells under cytokine stimulation. M1 macrophages are pro-inflammatory and secrete pro-inflammatory cytokines, while the M2 main phenotype is essentially anti-inflammatory and promotes tissue repair. Conversely, MoMacs undergo differentiation into M1 or M2 cells in response to cytokine stimulation. M1 macrophages are considered pro-inflammatory cells and secrete pro-inflammatory mediators, whereas the M2 main phenotype is primarily anti-inflammatory and promotes tissue repair. Moreover, based on cytokine expression, M2 macrophages can be further divided into M2a, M2b, and M2c phenotypes. M2a and M2c have anti-inflammatory effects and participate in tissue repair, while M2b cells have immunoregulatory and pro-inflammatory properties. Further, memory macrophages also have a role in the advancement of LN. Studies have demonstrated that the polarization of macrophages is controlled by multiple metabolic pathways, such as glycolysis, the pentose phosphate pathway, fatty acid oxidation, sphingolipid metabolism, the tricarboxylic acid cycle, and arginine metabolism. The changes in these metabolic pathways can be regulated by substances such as fish oil, polyenylphosphatidylcholine, taurine, fumaric acid, metformin, and salbutamol, which inhibit M1 polarization of macrophages and promote M2 polarization, thereby alleviating LN. Highlights: Macrophages are the main infiltrating cells in lupus nephritis (LN) kidneys. Different macrophage subtypes have different effects on the development and progression of LN. M1-type macrophages possess pro-inflammatory functions, participating in the onset and progression of LN. In contrast, M2-type macrophages primarily exhibit anti-inflammatory and tissue repair-promoting functions, which are beneficial for the remission of LN. The infiltration of mixed phenotype macrophages reflects a failure in the resolution of inflammation and correlates with poor prognostic outcomes in LN. Multiple metabolic pathways, such as glycolysis, pentose phosphate pathway, amino sugar and nucleotide sugar metabolism, fatty acid oxidation, sphingolipid metabolism, tricarboxylic acid cycle, arginine metabolism, and tryptophan metabolism, regulate macrophage polarization. Compounds such as omega-3 fatty acids, polyunsaturated phospholipids, taurine, fumarate, metformin, salbutamol, and others can modulate metabolic pathways, suppressing M1 polarization and promoting M2 polarization in macrophages, thereby ameliorating LN symptoms.
- Subjects
METABOLIC reprogramming; KREBS cycle; PENTOSE phosphate pathway; FATTY acid oxidation; OMEGA-3 fatty acids
- Publication
Molecular Medicine, 2024, Vol 30, Issue 1, p1
- ISSN
1076-1551
- Publication type
Article
- DOI
10.1186/s10020-024-00866-z