Regulation of Marginal Zone B-Cell Differentiation by MicroRNA-146a

King, Jennifer K.; Ung, Nolan; Paing, May; Contreras, Jorge R.; Alberti, Michael O.; Fernando, Thilini R.; Zhang, Kelvin; Pellegrini, Matteo; Rao, Dinesh S.

doi:10.3389/fimmu.2016.00670

Cited by 25 publications

(26 citation statements)

References 28 publications

(57 reference statements)

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“…Notch signaling has been found to be directly affected by miR-146a in many tissues [ 62 , 63 , 64 ]. Our transcriptomics and proteomics data confirmed by western blot analysis, along with in silico analysis of miR-146a-predicted targets with the presence of miR-146a binding site in Notch-2- and Numb 3′-UTRs [ 45 ], suggest that both Numb and Notch-2 are novel targets of miR-146a in human primary LECs and organ-cultured corneas ( Supplementary Tables S1 and S2 , Figure 5 and Figure 6 ). Overexpression of miR-146a induced repression of Numb and an increase in Notch-1 expression level, which is in agreement with earlier verified miR-146a direct target studies [ 63 , 64 , 65 ].…”

Section: Discussionsupporting

confidence: 57%

“…miR-146a is an important regulator of many cellular functions and targets different genes in different cell types [ 40 , 41 , 42 ]. It plays a major role in several diseases, such as diabetes [ 40 ], cancer [ 41 ], and Graves ophthalmopathy [ 42 ], and its association with different pathways suggests its involvement in cell migration [ 9 , 10 , 43 ], invasion [ 44 ], differentiation [ 45 ], and proliferation [ 44 ]. Our previous studies also revealed that miR-146a plays a regulatory role in corneal wound healing and limbal epithelial stem cell maintenance in normal and diabetic corneas [ 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

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Integrated Transcriptome and Proteome Analyses Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via Notch Signaling

Poe

Kulkarni

Leszczynska

et al. 2020

Cells

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MiR-146a is upregulated in the stem cell-enriched limbal region vs. central human cornea and can mediate corneal epithelial wound healing. The aim of this study was to identify miR-146a targets in human primary limbal epithelial cells (LECs) using genomic and proteomic analyses. RNA-seq combined with quantitative proteomics based on multiplexed isobaric tandem mass tag labeling was performed in LECs transfected with miR-146a mimic vs. mimic control. Western blot and immunostaining were used to confirm the expression of some targeted genes/proteins. A total of 251 differentially expressed mRNAs and 163 proteins were identified. We found that miR-146a regulates the expression of multiple genes in different pathways, such as the Notch system. In LECs and organ-cultured corneas, miR-146a increased Notch-1 expression possibly by downregulating its inhibitor Numb, but decreased Notch-2. Integrated transcriptome and proteome analyses revealed the regulatory role of miR-146a in several other processes, including anchoring junctions, TNF-α, Hedgehog signaling, adherens junctions, TGF-β, mTORC2, and epidermal growth factor receptor (EGFR) signaling, which mediate wound healing, inflammation, and stem cell maintenance and differentiation. Our results provide insights into the regulatory network of miR-146a and its role in fine-tuning of Notch-1 and Notch-2 expressions in limbal epithelium, which could be a balancing factor in stem cell maintenance and differentiation.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome and Proteome Analyses Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via Notch Signaling

Poe

Kulkarni

Leszczynska

et al. 2020

Cells

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“…Marginal zone B cells and FOB exhibit different gene expression profiles ( 18 , 19 ), which contribute to their differential localization and function. MZB have an IgM high IgD low CD21 high CD23 − CD1d high phenotype ( 20 ), which is distinct from FOB that are IgM low IgD high CD21 low CD23 high CD1d − .…”

Section: Introductionmentioning

confidence: 99%

Fcµ Receptor Promotes the Survival and Activation of Marginal Zone B Cells and Protects Mice against Bacterial Sepsis

Zhu

Qian

et al. 2018

Front. Immunol.

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The marginal zone B cells (MZB) are located at the interface between the circulation and lymphoid tissue and as a gatekeeper play important roles in both innate and adaptive immune responses. We have previously found that MZB are significantly reduced in mice deficient in the IgM Fc receptor (FcμR) but how FcμR regulates the development and function of MZB remains unknown. In this study, we found that both marginal zone precursor (MZP) and MZB were decreased in FcμR−/− mice. The reduction of MZP and MZB was not due to impaired proliferation of these cells but rather due to their increased death. Further analysis revealed that FcμR−/− MZB had reduced tonic BCR signal, as evidenced by their decreased levels of phosphorylated SYK and AKT relative to WT MZB. MZB in FcμR−/− mice responded poorly to LPS in vivo when compared with MZB in WT mice. Consistent with the reduced proportion of MZB and their impaired response to LPS, antibody production against the type 1 T-independent Ag, NP-LPS, was significantly reduced in FcμR−/− mice. Moreover, FcμR−/− mice were highly susceptible to Citrobacter rodentium-induced sepsis. These results reveal a critical role for FcμR in the survival and activation of MZB and in protection against acute bacterial infection.

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“…For example, King et al [46] reported that miR-146 is an important regulator of Notch2 signaling which influences the development of marginal-zone (MZ) B cells by targeting the Numb gene. Furthermore, miR-205 can maintain T cell development by regulating Forkhead box N1 (FOXN1), in the condition of a changed thymic microenvironment induced by stress such as infections, radiation exposure, and steroids [47].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-126 Deficiency Affects the Development of Thymus CD4<sup>+</sup> Single-Positive Cells through Elevating IRS-1

et al. 2018

Int Arch Allergy Immunol

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Background: MicroRNA-126 (miR-126), a distinct miRNA family member, has been reported to be involved in the development and function of some types of immune cells. However, the potential role of miR-126 in the development of CD4⁺ T cells remains to be elucidated. Objectives: To investigate the potential role of miR-126 in the development of CD4⁺ T cells in the thymus and explore its significance. Methods: The relative expression level of miR-126 in thymus CD4⁺ single-positive (SP) cells was detected by Real-Time PCR assay. The possible change in thymus tissue was assessed by histopathology. The total cell number of thymocytes and the expression of activation-associated molecules including CD62L, CD69, and CD44, as well as proliferation-associated nuclear antigen Ki-67, in CD4⁺ SP cells were assessed by flow cytometric analysis. The expression of IRS-1 and related signaling pathways including Akt and Erk were determined by flow cytometric analysis. Results: Compared with that in wild-type (WT) mice, the total cell number of thymocytes in miR-126 knockdown (KD) mice increased significantly. Moreover, the proportion and absolute cell number of thymic CD4⁺ SP cells decreased significantly in miR-126 KD mice. Further analysis showed that the frequencies of activation-associated molecules including CD62L, CD69, and CD44, as well as proliferation-associated nuclear antigen Ki-67 in CD4⁺ SP cells also changed significantly, respectively. Mechanism aspect, the expression level of IRS-1, a putative target of miR-126, increased significantly in CD4⁺ SP cells in miR-126 KD mice. Moreover, the expression levels of the signaling molecules phosphorylated (p)-Akt and p-Erk also changed significantly. Conclusions: Our work is the first to reveal a previously unknown role of miR-126 in the development of CD4⁺ SP cells in the thymus, which might ultimately benefit studies on development of thymocytes.

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Regulation of Marginal Zone B-Cell Differentiation by MicroRNA-146a

Cited by 25 publications

References 28 publications

Integrated Transcriptome and Proteome Analyses Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via Notch Signaling

Integrated Transcriptome and Proteome Analyses Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via Notch Signaling

Fcµ Receptor Promotes the Survival and Activation of Marginal Zone B Cells and Protects Mice against Bacterial Sepsis

MicroRNA-126 Deficiency Affects the Development of Thymus CD4<sup>+</sup> Single-Positive Cells through Elevating IRS-1

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