MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response

Essandoh, Kobina; Li, Yutian; Huo, Jiuzhou; Fan, Guo-Chang

doi:10.1097/shk.0000000000000604

Cited by 492 publications

(430 citation statements)

References 97 publications

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“…These findings were also reported by Yang and fellow workers in an earlier study [126]. miRNA profiles and levels also regulate the inflammatory status and polarisation of macrophages via several different mechanisms including NF-κB transcription and cellular location [127,128].…”

Section: Epigenetic Changes In Peripheral Mononuclear Blood Cellssupporting

confidence: 70%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

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Section: Epigenetic Changes In Peripheral Mononuclear Blood Cellssupporting

confidence: 70%

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

et al. 2018

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“…These functions are mainly achieved by the binding of mi-RNAs with the 3'-UTR of mRNAs [11]. MiRNAs have recently been implicated in inflammatory responses, sepsis, and, specifically, macrophage activities [9,[12][13][14]. MicroRNA-138 (miR-138) is reported to participate in oncogenesis and axon regeneration, but it is not clear whether miR-138 plays a role in inflammation or sepsis [15,16].…”

Section: Introductionmentioning

confidence: 99%

“…These inflammatory factors are also important cytokines increased in sepsis during severe inflammatory periods. M2 macrophages (or alternatively activated macrophages) are anti-inflammatory macrophages that depend on the activation of STAT6 or AKT pathways [9,10]. MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression by binding to mRNA, stopping translation or degrading the mRNAs.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-138 Aggravates Inflammatory Responses of Macrophages by Targeting SIRT1 and Regulating the NF-κB and AKT Pathways

Bai

Zhang

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: With increased understanding of sepsis, mortality is decreasing. However, there is still a lack of effective therapeutic strategy. The inflammatory response of macrophages is critical during sepsis. Methods: Macrophages were stimulated with LPS. Western blotting and qRT-PCR were used to detect inflammatory responses. Then, the inhibitor of microRNA-138 was transfected and Western blotting, qRT-PCR, H&E staining and ELISA were used to verify the role of microRNA-138 in inflammation. Then target gene prediction databases were used to predict the potential target of microRNA-138. Both animal and cell models under LPS challenges were established to verify the regulation of SIRT1 and microRNA-138 during inflammation. Results: The present study showed that microRNA-138 was increased in macrophages stimulated with LPS. Additionally, the NF-κB and AKT pathways were both activated. The pre-treatment of microRNA-138 inhibitor decreased inflammatory factors, downregulated the NF-κB pathway, activated the AKT pathway and protected against organ damage in mice challenged with LPS. SIRT1 was demonstrated as a potential target of microRNA-138In macrophages stimulated with LPS, the inhibition effect of microRNA-138 inhibitor on inflammation was lost by SIRT1 siRNA pre-treatment. In the animal model, the protective effect of microRNA-138 antagomir disappeared in SIRT1 knockout mice. Conclusion: We demonstrated that miR-138 participated in the inflammatory process by inhibiting SIRT1 and activating the NF-κB pathway.

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“…63 In macrophages, miR-34a promotes M2 polarization linked to immunosuppression. 64 Therefore, age-related overexpression of miR-34a seems to be an important pro-inflammatory immunoaging-contributing factor. However, our findings also show that the negative effect of excess miR-34a in PBMC of aged humans does not depend mainly on its inhibitory effect on SIRT1, as downregulation of SIRT1 was detected also in longlived study subjects who did not suffer from aging-related diseases.…”

Section: Discussionmentioning

confidence: 99%

“…67 In contrast to miR-34a, miR-9 induces M1 polarization of macrophages, which is associated with the production of pro-inflammatory cytokines. 64,68 Therefore, in addition to its role in immunoaging exerted via SIRT1, other miR-9 mechanisms are involved in this process. Nevertheless, its overexpression in PBMC of long-lived humans suggests that it is not detrimental, at least in individuals who age successfully.…”

Section: Discussionmentioning

confidence: 99%

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

Owczarz

Budzinska

Domaszewska-Szostek

et al. 2017

Exp Biol Med (Maywood)

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Impact statementHigh expression of sirtuins, particularly SIRT1, lowers the risk of age-related diseases and probably slows down the rate of aging; therefore, their sustained expression should be one of the features of longevity. However, in this work we show that in peripheral blood mononuclear cells (PBMC) of long-lived individuals, expression of majority of the SIRT genes is significantly lower than in cells of young study subjects. In long-lived individuals, downregulation of SIRT1 coexists with upregulation of SIRT1 mRNA-interacting miR-34a and miR-9, indicating the role of epigenetic drift in age-dependent deregulation of SIRT1 expression. Such constellation of SIRT1, miR-34a, and miR-9 expression in PBMC of successfully aging long-lived individuals indicates that, at least in these individuals, it is not a risk factor for morbidity and mortality. It might however affect the function of the immune system and, therefore, aging individuals can profit from interventions increasing the level of SIRT1. AbstractIncreased expression of sirtuins lowers the risk of age-related diseases, while their role in the regulation of longevity is not firmly established. Since aging is associated with immunosenescence, we tested whether sirtuin expression was modified in peripheral blood mononuclear cells (PBMC) in an age-related manner and whether this might result from altered expression of the selected miRNAs. The expression of seven SIRT genes and of SIRT1 mRNA-interacting miR-9, miR-34a, miR-132, and miR-199a-5p was evaluated by real-time PCR in PBMC originating from young (Y, n ¼ 57, mean age 27 AE 4.3 years), elderly (E, n ¼ 52, 65 AE 3.4 years), and long-lived (L, n ¼ 56, 94 AE 3.5 years) individuals. Older age was associated with a decreased expression of the majority of the SIRT genes. Most severely affected were median expressions of SIRT1 (P ¼ 0.000001 for the whole studied group, Y vs. E: P < 0.000001, Y vs. L: P < 0.000001), and of SIRT3 (P ¼ 0.000001, Y vs. E: P ¼ 0.000004, Y vs. L: P ¼ 0.000028). Older age was also associated with the increased median expression of miR-34a (P ¼ 0.000001, Y vs. E: P ¼ 0.001, Y vs. L: P ¼ 0.000004) and of miR-9 (P ¼ 0.05, Y vs. L: P ¼ 0.054). In functional studies, miR-9 interacted with the 3 0 UTR of SIRT1 mRNA. The SIRT1 mRNA level negatively correlated with the expression of miR34a (r ¼ À0.234, P ¼ 0.003). In conclusion, age-related decrease of SIRT1 expression in PBMC might in part result from overexpression of miR-34a and miR-9. In addition, the sustained expression of the SIRT genes in PBMC is not a prerequisite to longevity in humans but might be one of the reasons for the immune system dysfunction in the elderly.

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MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response

Cited by 492 publications

References 97 publications

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

Could Alzheimer’s Disease Originate in the Periphery and If So How So?

MicroRNA-138 Aggravates Inflammatory Responses of Macrophages by Targeting SIRT1 and Regulating the NF-κB and AKT Pathways

miR-34a and miR-9 are overexpressed and SIRT genes are downregulated in peripheral blood mononuclear cells of aging humans

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