Important role of mechanical microenvironment on macrophage dysfunction during keloid pathogenesis

Zhou, Boya; Gao, Zhen; Liu, Wei; Wu, Xiaoli; Wang, Wenbo

doi:10.1111/exd.14473

Cited by 13 publications

(12 citation statements)

References 33 publications

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“…Transcriptome analysis showed that the core differentially expressed genes related to collagen synthesis play a vital role in the pathogenesis of keloids, including COL1A, COL1A2, COL5A2, and COL3A1. The analysis of the keloid immune microenvironment revealed the infiltration of immune cells around fibroblasts, which directly or indirectly affected the proliferation of fibroblasts ( Zhou et al, 2021 ). The expression of NNMT, AOX1, PLOD1, PLOD2, and PLOD3 at the transcription level is consistent with the metabolome sequencing data ( Supplementary Figure S2 ).…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Reveals That 5-Hydroxylysine and 1-Methylnicotinamide Are Metabolic Indicators of Keloid Severity

et al. 2022

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Background: Keloid is a skin fibroproliferative disease with unknown pathogenesis. Metabolomics provides a new perspective for revealing biomarkers related to metabolites and their metabolic mechanisms.Method: Metabolomics and transcriptomics were used for data analysis. Quality control of the data was performed to standardize the data. Principal component analysis (PCA), PLS-DA, OPLS-DA, univariate analysis, CIBERSORT, neural network model, and machine learning correlation analysis were used to calculate differential metabolites. The molecular mechanisms of characteristic metabolites and differentially expressed genes were identified through enrichment analysis and topological analysis.Result: Compared with normal tissue, lipids have a tendency to decrease in keloids, while peptides have a tendency to increase in keloids. Significantly different metabolites between the two groups were identified by random forest analysis, including 1-methylnicotinamide, 4-hydroxyproline, 5-hydroxylysine, and l-prolinamide. The metabolic pathways which play important roles in the pathogenesis of keloids included arachidonic acid metabolism and d-arginine and d-ornithine metabolism. Metabolomic profiling reveals that 5-hydroxylysine and 1-methylnicotinamide are metabolic indicators of keloid severity. The high-risk early warning index for 5-hydroxylysine is 4 × 108-6.3×108 (p = 0.0008), and the high-risk predictive index for 1-methylnicotinamide is 0.95 × 107-1.6×107 (p = 0.0022).Conclusion: This study was the first to reveal the metabolome profile and transcriptome of keloids. Differential metabolites and metabolic pathways were calculated by machine learning. Metabolomic profiling reveals that 5-hydroxylysine and 1-methylnicotinamide may be metabolic indicators of keloid severity.

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Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling Reveals That 5-Hydroxylysine and 1-Methylnicotinamide Are Metabolic Indicators of Keloid Severity

et al. 2022

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“…M2 macrophages are disproportionally elevated in keloid lesions ( 69 – 72 , 74 ), in part due to local enrichment of Th2 cytokines. Although not yet verified, M2 dominance has also been linked to macrophage sensitivity to mechanical signals, including skin tension and stiffness ( 42 ). M2 macrophages initiate wound closure via secretion of TGF-β1, a potent inducer of both fibroblast proliferation and their differentiation into myofibroblasts ( 115 ).…”

Section: The Roles Of Immune Cells In Keloid Formationmentioning

confidence: 99%

An updated review of the immunological mechanisms of keloid scars

et al. 2023

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Keloid is a type of disfiguring pathological scarring unique to human skin. The disorder is characterized by excessive collagen deposition. Immune cell infiltration is a hallmark of both normal and pathological tissue repair. However, the immunopathological mechanisms of keloid remain unclear. Recent studies have uncovered the pivotal role of both innate and adaptive immunity in modulating the aberrant behavior of keloid fibroblasts. Several novel therapeutics attempting to restore regulation of the immune microenvironment have shown variable efficacy. We review the current understanding of keloid immunopathogenesis and highlight the potential roles of immune pathway-specific therapeutics.

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“…It is believed that pathological scars are caused by excessive and persistent inflammation, and the intensity of inflammation is positively correlated with the final scar size ( Huang et al, 2014 ). Various inflammatory cells, including ( Zhou et al, 2021 ), mast cells ( Bagabir et al, 2012 ), lymphocytes ( Chen et al, 2018 ), and monocytes ( Limandjaja et al, 2019 ), have been reported to be involved in keloid formation. Among these, macrophages are important cells that initiate an inflammatory response during wound healing and lead to excessive spreading of inflammation.…”

Section: Keloid Pathogenesis Studymentioning

confidence: 99%

Biomechanical Regulatory Factors and Therapeutic Targets in Keloid Fibrosis

et al. 2022

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Keloids are fibroproliferative skin disorder caused by abnormal healing of injured or irritated skin and are characterized by excessive extracellular matrix (ECM) synthesis and deposition, which results in excessive collagen disorders and calcinosis, increasing the remodeling and stiffness of keloid matrix. The pathogenesis of keloid is very complex, and may include changes in cell function, genetics, inflammation, and other factors. In this review, we aim to discuss the role of biomechanical factors in keloid formation. Mechanical stimulation can lead to excessive proliferation of wound fibroblasts, deposition of ECM, secretion of more pro-fibrosis factors, and continuous increase of keloid matrix stiffness. Matrix mechanics resulting from increased matrix stiffness further activates the fibrotic phenotype of keloid fibroblasts, thus forming a loop that continuously invades the surrounding normal tissue. In this process, mechanical force is one of the initial factors of keloid formation, and matrix mechanics leads to further keloid development. Next, we summarized the mechanotransduction pathways involved in the formation of keloids, such as TGF-β/Smad signaling pathway, integrin signaling pathway, YAP/TAZ signaling pathway, and calcium ion pathway. Finally, some potential biomechanics-based therapeutic concepts and strategies are described in detail. Taken together, these findings underscore the importance of biomechanical factors in the formation and progression of keloids and highlight their regulatory value. These findings may help facilitate the development of pharmacological interventions that can ultimately prevent and reduce keloid formation and progression.

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Important role of mechanical microenvironment on macrophage dysfunction during keloid pathogenesis

Cited by 13 publications

References 33 publications

Metabolomic Profiling Reveals That 5-Hydroxylysine and 1-Methylnicotinamide Are Metabolic Indicators of Keloid Severity

Metabolomic Profiling Reveals That 5-Hydroxylysine and 1-Methylnicotinamide Are Metabolic Indicators of Keloid Severity

An updated review of the immunological mechanisms of keloid scars

Biomechanical Regulatory Factors and Therapeutic Targets in Keloid Fibrosis

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