MicroRNA-10a-3p mediates Th17/Treg cell balance and improves renal injury by inhibiting REG3A in lupus nephritis

You, Guoxiang; Cao, Huixia; Liang, Yan; He, Pan; Wang, Yanliang; Liu, Bing; Shao, Fengmin

doi:10.1016/j.intimp.2020.106891

Cited by 22 publications

(16 citation statements)

References 23 publications

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“…Thus, the immunomodulatory efficacy of stem cell therapies (either Umbilical cord, Bone Marrow or adipose-derived) involves the suppression of the axis or restoration of the Treg/Th17 balance (12,154); and defects in the functioning of stem cells trigger the disease (121). The beneficial effect of specific MicroRNA as miR-125a-3p and MicroRNA-10a-3p also involve interference on the axis (153,264). In an experimental study, punicalagin (a bioactive antagonist of PAR2) ameliorated lupus nephritis, in association with a significant reduction in splenic Th17 populations compared to the vehicle controls (265).…”

Section: Agents Targeting Indirectly the Th17/il-17 Axis And Related Pathwaysmentioning

confidence: 99%

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Paquissi

Abensur

2021

Front. Med.

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Systemic lupus erythematosus (SLE) is a disease characterized by dysregulation and hyperreactivity of the immune response at various levels, including hyperactivation of effector cell subtypes, autoantibodies production, immune complex formation, and deposition in tissues. The consequences of hyperreactivity to the self are systemic and local inflammation and tissue damage in multiple organs. Lupus nephritis (LN) is one of the most worrying manifestations of SLE, and most patients have this involvement at some point in the course of the disease. Among the effector cells involved, the Th17, a subtype of T helper cells (CD4+), has shown significant hyperactivation and participates in kidney damage and many other organs. Th17 cells have IL-17A and IL-17F as main cytokines with receptors expressed in most renal cells, being involved in the activation of many proinflammatory and profibrotic pathways. The Th17/IL-17 axis promotes and maintains repetitive tissue damage and maladaptive repair; leading to fibrosis, loss of organ architecture and function. In the podocytes, the Th17/IL-17 axis effects include changes of the cytoskeleton with increased motility, decreased expression of health proteins, increased oxidative stress, and activation of the inflammasome and caspases resulting in podocytes apoptosis. In renal tubular epithelial cells, the Th17/IL-17 axis promotes the activation of profibrotic pathways such as increased TGF-β expression and epithelial-mesenchymal transition (EMT) with consequent increase of extracellular matrix proteins. In addition, the IL-17 promotes a proinflammatory environment by stimulating the synthesis of inflammatory cytokines by intrinsic renal cells and immune cells, and the synthesis of growth factors and chemokines, which together result in granulopoiesis/myelopoiesis, and further recruitment of immune cells to the kidney. The purpose of this work is to present the prognostic and immunopathologic role of the Th17/IL-17 axis in Kidney diseases, with a special focus on LN, including its exploration as a potential immunotherapeutic target in this complication.

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Section: Agents Targeting Indirectly the Th17/il-17 Axis And Related Pathwaysmentioning

confidence: 99%

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Paquissi

Abensur

2021

Front. Med.

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“…During the revision of our manuscript, You et al . reported that REG3A inhibition by miRNA (MiR‐10a‐3p) in human T cells is able to shift the balance between Th17/Treg in favour of the latter [65]. The role for murine Reg3γ is unclear from this work; nevertheless, this study underlines that Reg family members may have direct impact on CD4 + T‐cell lineage choices.…”

Section: Discussionmentioning

confidence: 81%

Temporal overexpression of IL‐22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis

et al. 2021

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IL‐22 is an alpha‐helical cytokine which belongs to the IL‐10 family of cytokines. IL‐22 is produced by RORγt+ innate and adaptive lymphocytes, including ILC3, γδ T, iNKT, Th17 and Th22 cells and some granulocytes. IL‐22 receptor is expressed primarily by non‐haematopoietic cells. IL‐22 is critical for barrier immunity at the mucosal surfaces in the steady state and during infection. Although IL‐22 knockout mice were previously shown to develop experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), how temporal IL‐22 manipulation in adult mice would affect EAE course has not been studied previously. In this study, we overexpressed IL‐22 via hydrodynamic gene delivery or blocked it via neutralizing antibodies in C57BL/6 mice to explore the therapeutic impact of IL‐22 modulation on the EAE course. IL‐22 overexpression significantly decreased EAE scores and demyelination, and reduced infiltration of IFN‐γ+IL‐17A+Th17 cells into the central nervous system (CNS). The neutralization of IL‐22 did not alter the EAE pathology significantly. We show that IL‐22‐mediated protection is independent of Reg3γ, an epithelial cell‐derived antimicrobial peptide induced by IL‐22. Thus, overexpression of Reg3γ significantly exacerbated EAE scores, demyelination and infiltration of IFN‐γ+IL‐17A+ and IL‐17A+GM‐CSF+Th17 cells to CNS. We also show that Reg3γ may inhibit IL‐2‐mediated STAT5 signalling and impair expansion of Treg cells in vivo and in vitro. Finally, Reg3γ overexpression dramatically impacted intestinal microbiota during EAE. Our results provide novel insight into the role of IL‐22 and IL‐22‐induced antimicrobial peptide Reg3γ in the pathogenesis of CNS inflammation in a murine model of MS.

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“…Overexpressed miR-21 tended to polarize T cell differentiation towards the T H 17 phenotype at the expense of regulatory T cells, and also regulates T-cell co-stimulation including CD40:CD154 and CD28:CD80/86. One study showed decreased miR-10a-3p in PBMCs of LN patients, which increased the T H 17/Treg ratio in CD4 + T cells via upregulation of regenerating islet-derived 3 α (REG3A), and also activated the JAK2/STAT3 signalling pathway downstream [ 34 ]. In murine lupus models, systemic administration of miR-10a-3p reversed these changes and also improved renal function, 24-h urine protein, markers of renal injury such as kidney injury molecule-1 (KIM-1) and decreased anti-dsDNA levels.…”

Section: Mirs In the Circulation And Peripheral Blood Mononuclear Cells (Pbmcs)mentioning

confidence: 99%

MicroRNAs in Lupus Nephritis–Role in Disease Pathogenesis and Clinical Applications

Yap

Chan

2021

IJMS

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MicroRNAs (miRs) are non-coding small RNAs that act as epigenetic modulators to regulate the protein levels of target mRNAs without modifying the genetic sequences. The role of miRs in the pathogenesis of lupus nephritis (LN) is increasingly recognized and highly complex. Altered levels of different miRs are observed in the blood, urine and kidney tissues of murine LN models and LN patients. Accumulating evidence suggests that these miRs can modulate immune cells and various key inflammatory pathways, and their perturbations contribute to the aberrant immune response in LN. The dysregulation of miRs in different resident renal cells and urinary exosomes can also lead to abnormal renal cell proliferation, inflammation and kidney fibrosis in LN. While miRs may hold promise in various clinical applications in LN patients, there are still many potential limitations and safety concerns for their use. Further studies are worthwhile to examine the clinical utility of miRs in the diagnosis, disease activity monitoring, prognostication and treatment of LN.

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MicroRNA-10a-3p mediates Th17/Treg cell balance and improves renal injury by inhibiting REG3A in lupus nephritis

Cited by 22 publications

References 23 publications

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

The Th17/IL-17 Axis and Kidney Diseases, With Focus on Lupus Nephritis

Temporal overexpression of IL‐22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis

MicroRNAs in Lupus Nephritis–Role in Disease Pathogenesis and Clinical Applications

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