miR-122-SOCS1-JAK2 axis regulates allergic inflammation and allergic inflammation-promoted cellular interactions

Lee²,

et al. 2018

Front. Pharmacol.

Self Cite

The objective of this study was to investigate the effect of human adipose tissue-derived mesenchymal stem cells (AdMSCs) on atopic dermatitis (AD) in the BALB/c mouse model. The AdMSCs attenuated clinical symptoms associated with AD, decreased numbers of degranulated mast cells (MCs), IgE level, amount of histamine released, and prostaglandin E2 level. Atopic dermatitis increased the expression levels of cytokines/chemokines, such as interleukin-5 (IL-5), macrophage inflammatory protein-1ß (MIP-1ß), MIP-2, chemokine (C-C motif) ligand 5 (CCL5), and IL-17, in BALB/c mouse. The AdMSCs showed decreased expression levels of these cytokines in the mouse model of AD. In vivo downregulation of MIP-2 attenuated the clinical symptoms associated with AD. Atopic dermatitis increased the expression levels of hallmarks of allergic inflammation, induced interactions of Fc𝜀RIβ with histone deacetylase 3 (HDAC3) and Lyn, increased ß-hexosaminidase activity, increased serum IgE level, and increased the amount of histamine released in an MIP-2-dependent manner. Downregulation of MIP-2 increased the levels of several miRNAs, including miR-122a-5p. Mouse miR-122a-5p mimic inhibited AD, while suppressor of cytokine signaling 1 (SOCS1), a predicted downstream target of miR-122a-5p, was required for AD. The downregulation of SOCS1 decreased the expression levels of MIP-2 and chemokine (C-X-C motif) ligand 13 (CXCL13) in the mouse model of AD. The downregulation of CXCL13 attenuated AD and allergic inflammation such as passive cutaneous anaphylaxis. The role of T cell transcription factors in AD was also investigated. Atopic dermatitis increased the expression levels of T-bet and GATA-3 [transcription factors of T-helper 1 (Th1) and T-helper 2 (Th2) cells, respectively] but decreased the expression of Foxp3, a transcription factor of regulatory T (Treg) cells, in an SOCS1-dependent manner. In addition to this, miR-122a-5p mimic also prevented AD from regulating the expression of T-bet, GATA-3, and Foxp3. Atopic dermatitis increased the expression of cluster of differentiation 163 (CD163), a marker of M2 macrophages, but decreased the expression of inducible nitric oxide synthase (iNOS), a marker of M1 macrophages. Additionally, SOCS1 and miR-122a-5p mimic regulated the expression of CD163 and iNOS in the mouse model of AD. Experiments employing conditioned medium showed interactions between MCs and macrophages in AD. The conditioned medium of AdMSCs, but not the conditioned medium of human dermal fibroblasts, negatively inhibited the features of allergic inflammation. In summary, we investigated the anti-atopic effects of AdMSCs, identified targets of AdMSCs, and determined the underlying mechanism for the anti-atopic effects of AdMSCs.

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Human Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Atopic Dermatitis by Regulating the Expression of MIP-2, miR-122a-SOCS1 Axis, and Th1/Th2 Responses

Lee²,

et al. 2018

Front. Pharmacol.

Self Cite

“…More than 2,000 miRNAs have been discovered in human cells, and it is believed that they participate in the occurrence and development of multiple human diseases, including pressure ulcers (Hammond, ; Tufekci, Oner, Meuwissen, & Genc, ; R. Yang, Han, & Zeng, ). miRNA‐122 (miR‐122) has been found to play key roles in the regulation of inflammatory response in a variety of human diseases, including skin diseases (Noh et al, ; Roderburg et al, ). Jiang et al () indicated that miR‐122 was involved in the regulation of keratinocyte proliferation by targeting Sprouty 2.…”

Section: Introductionmentioning

confidence: 99%

Retracted: Tanshinol relieves lipopolysaccharide‐induced inflammatory injury of HaCaT cells via down‐regulation of microRNA‐122

Wang

Wei²

2019

Phytotherapy Research

This study investigated the effects of tanshinol (TAN) on lipopolysaccharide (LPS)induced human keratinocytes inflammatory injury and underlying potential molecular mechanisms. Viability and apoptosis of HaCaT cells were assessed using MTT assay and Annexin V-FITC/PI staining, respectively. Quantitative reverse transcription-polymerase chain reaction was performed to measure the expression of microRNA-122 (miR-122) in HaCaT cells. Cell transfection was conducted to up-regulate the expression of miR-122. Western blotting was used to detect the protein expression levels of key factors involved in cell apoptosis, inflammatory response, c-Jun N-terminal kinase (JNK), and nuclear factor kappa B (NF-κB) pathways. We found that LPS treatment induced HaCaT cell inflammatory injury by inhibiting cell viability, promoting cell apoptosis, and enhancing the protein expression levels of cyclooxygenase 2 and inducible nitric oxide synthase. TAN treatment relieved LPS-induced HaCaT cell inflammatory injury. Moreover, TAN treatment attenuated LPS-induced activation of JNK and NF-κB pathways in HaCaT cells. Furthermore, TAN treatment alleviated LPS-induced up-regulation of miR-122. Overexpression of miR-122 reversed the effects of TAN on LPS-induced HaCaT cell inflammatory injury and activation of JNK and NF-κB pathways. In conclusion, TAN exerted anti-inflammatory and protective effects on keratinocytes injury. TAN relieved LPS-induced inflammatory injury of human HaCaT cells via downregulating miR-122 and then inactivating JNK and NF-κB pathways.

Cell Biochemistry & Function

“…Previous studies confirmed that miR‐122 could downregulate the TGF‐β related pathways, such as the TGF‐β/suppressor of cytokine signalling 1‐Janus kinase 2 (SOCS1‐JAK2) pathway and TGF‐β/Smad pathway. Since the inhibition of TGF‐β promotes muscle regeneration, it is possible that miR‐122 participates in myogenesis through downregulating the TGF‐β/Smad signalling pathway.…”

Section: Introductionmentioning

confidence: 99%

miR‐122‐5p negatively regulates the transforming growth factor‐β/Smad signaling pathway in skeletal muscle myogenesis

Ding

Lin

Sun

et al. 2019

Regeneration remains a major challenge in skeletal muscle repair after injury.Recently, transforming growth factor-β (TGF-β)/Smad pathway was found to play an important role in inhibiting myogenesis, a crucial stage in skeletal muscle regeneration. In our previous study, microRNA-122-5p (miR-122) was proved to have the function of downregulating TGF-β/Smad pathway. Theoretically, miR-122 might also be involved in the process of skeletal muscle myogenesis through the regulation of TGF-β/Smad pathway. In this study, we aimed to investigate the impact of miR-122 on skeletal muscle myogenesis and explore its underlying mechanism. Results showed that miR-122 and myogenic markers were downregulated in C2C12 cells after TGF-β stimulation, and miR-122 overexpression could restore the myogenesis inhibited by TGF-β. We then located TGFBR2 as the direct target of miR-122 and discovered the effect of miR-122 overexpression could be rescued by TGFBR2 overexpression. Further, the downstream molecules of TGFBR2 in the TGF-β/Smad pathway were found to be suppressed by miR-122. In conclusion, miR-122 could suppress the TGF-β/Smad signalling pathway by directly targeting TGFBR2 and, consequently, restore myogenesis.Significance of the study: Regeneration remains a major challenge in skeletal muscle repair after injury. In this study, it was found that miR-122 could suppress the TGFβ/Smad signalling pathway by directly targeting TGFBR2 and, consequently, restore myogenesis. Our findings could inspire future experiments on the role of miRs in skeletal muscle diseases and future translational studies on potential novel gene therapy for skeletal muscle injury. K E Y W O R D SmiR-122, myogenesis, regeneration, skeletal muscle, Smad, TGFBR2, TGF-β