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General Commentary ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02649

Commentary on: MicroRNA-31 Reduces Inflammatory Signaling and Promotes Regeneration in Colon Epithelium, and Delivery of Mimics in Microspheres Reduces Colitis in Mice. DOI: 10.1053/j.gastro.2019.02.023. PMID: 30779922

Pooja Gupta1, Ravi P. Yadav2, Priya Rawat2 and  Somesh Baranwal2*
  • 1Guru Kashi University, India
  • 2Central University of Punjab, India

We read article published by Tian et al.[1] with great interest in deciphering molecular mechanisms and therapeutic potential of miR-31 mimic in progression of Inflammatory Bowel Disease (IBD). miR-31, located on chromosome 9p21.3, is a well-established locus that harbors tumor suppressor p15 and p16 to regulate mammalian cell cycle. Based on several reports, miR-31 can function as either oncogene or tumor suppressor in a context-dependent manner [2]. Moreover, mature miR-31-5p and miR-31-3p bind with various mRNA targets and play a functional role in regulating multiple diseases. In colorectal tissue and cells, miR-31 binds with 3’UTR of ERK5, RAS1, TGF-β, β-catenin, and several others mRNA to control radio-resistance, cell migration, and cell proliferation in-vitro and tumorigenesis and metastasis in-vivo in contrast, miR-31 show tumor suppressive role in gastric cancer to control Rho/ROCK and STAT3 signaling[3].
miR-31 is implicated in several inflammation-associated disorder. In IBD patients, miR-31 expression signature differentiates with Crohn’s disease, Ulcerative Colitis, microscopic colitis, and pediatric patients with inflammatory bowel disease. Further, miR-31 expression also controls colonic epithelial cell barrier function, CD8 T-cell response to type I IFN response during chronic infection. Also, miR-31 positively correlates with LGR5 positive cell to drive intestinal stem cell regeneration under stress condition. Moreover, overexpressing miR-31 in mouse demonstrate a significantly higher number of Intestinal Stem Cell (ISC) which was able to repair irradiation-induced cell damage[4]. In summary, miR-31 is a critical regulator of Wnt, BMP, and TGF-β signaling to control ISC proliferation, intestinal homeostasis, and colorectal cancer progression. Further, miR-31 also regulates keratinocyte differentiation and overexpressed in Psoriatic patients to regulate cytokine and chemokine production [5].
Tian and colleagues have delineated the precise molecular pathway of miR-31-5p activation in early inflammatory stage. They determined profound effect of miR-31-5p in the activation of canonical Wnt targets proteins and inhibition of Hippo signaling target proteins in inflammatory bowel disease progression, and epithelial regeneration in an in-vivo mouse model. Quantitative PCR analysis reveals a significant increase of miR-31-5p expression in Crohn’s disease (CD) and Ulcerative Colitis (CD) biopsies tissue which was reverting to the level of healthy control after remission. Treatment with Tumor Necrosis Factor (TNF), interleukin 6 (IL6) and DSS induced colitis enhances phosphorylation of STAT3 and p65 (NF-κB) which binds with miR-31 promoter sequence to activates it expression as determined by luciferase activity and chromatin immunoprecipitation in malignant LOVO cells line and organoid derived from mouse colon. In conclusion, inflammatory cytokines dynamically modulate miR-31-5p expression in an early inflammatory condition and DSS induced colitis in mouse and NF-κB signaling directly control miR-31-5p expression. Furthermore, the miR-31-5p level shows a positive correlation with a pathological marker for active UC and CD patients.
Several preclinical studies have demonstrated the potential activity of miRNA blockers in prevention of DSS or TNBS induced colitis in mouse model. Administration of these chemically modified anti-miRNA oligonucleotides (AMOs) through intracolonic, intraperitoneal, and tail vein injection attenuated colitis development, intestinal permeability, inflammatory score, and disease activity index [6]. Examination of germline knockout (KO) and villin-cre mediated colonic epithelial conditional knockdown (cKO) for miR-31 showed no apparent changes in cell proliferation, apoptosis, and a total number of goblet cells in the intestine while DSS induced colitis treatment show shorter colon length, larger spleen, and higher symptom of clinical disease. Moreover, miR-31 interact with 3’UTR of Interleukin 17 receptor A, Interleukin 6 Signal transducer and Interleukin- 7 receptor subunit alpha mRNA to control early immune response. Concomitantly, in-vivo permeability for miR-31 knockout is significantly reduced after three days of DSS treatment. In summary, their results reveal essential roles of miR-31 in suppressing the early inflammatory response after colitis induction.
Transcriptomics analysis of colonic epithelial cells from WT and miR-31 null showed significant changes in the sphingolipid metabolism, TGF-β, and canonical Wnt pathway. Further, there was significant inhibition of β-catenin, Cyclin D1, and Axin2 expression in null mice after colitis induction suggesting direct regulation of canonical Wnt signaling by miRNA-31. Next, they examined the Hippo signaling which is a critical mediator for tissue regeneration and found that Yap/p-YAP ratio was significantly reduced in miR-31 knockout suggesting the suppression of Hippo signaling following miR-31 activation. Moreover, there was significant upregulation of Lats2, Dlg1, and Dlg5 (downstream target gene of Hippo) following DSS colitis induction. Finally, they confirmed a similar signaling pathway in TNBS induced colitis (a model for Crohn’s disease) and rescuing effect following overexpressing miR-31 in in-vivo mouse model. In conclusion, they showed that miR-31 activates canonical Wnt signaling and inhibit Hippo signaling to control epithelial regeneration followed colitis induction.
Peptosomes are milk protein (α-lactalbumin) based delivery system which confers slow release of the drug molecule at the desired location with a minimal side effect[7]. This paper also highlights the proof in principles for encapsulating peptosome based miRNA mimic in novel light-responsive bioinspired TEMPO-oxidized Konjac Glucomannan (OKGM)[8] (named as OKGM-PS MIR-31 microsphere) into large intestine of mouse by injecting into the anus and testing its functions into both Wild type and miR-31 knockout mice induced with DSS colitis. Enema based treatment with OKGM-PS MIR-31 microsphere not only attenuate DSS induced colitis in miR-31 null mice but also play a protective role in wild type mice induced with colitis. Furthermore, OKGM-PS MIR-31 microsphere enhances cell proliferation, reduced immune response, and improve DSS induced epithelial cell integrity in wild type mice. It is not clear from their study how light-controlled activation step was performed before enema treatment. miR-31 mimic loaded in dual-layered microsphere seems to be an attractive tool for systemic delivery and slow release of the drug.
Overall, this paper delves into both upstream regulator and downstream effector protein of miR-31 which play a fundamental role in intestinal inflammation, epithelial cell regeneration, and novel delivery strategies for miRNA mimics for treating both UC and CD in a preclinical model. It will be interesting to see if miR-31 is involved in other types of mucosal inflammation. Future studies will unveil the efficacy and safety of this novel and straightforward delivery method of therapeutics in human clinical trials and pave the way for treating chronic inflammatory disease.

Keywords: miRNA - microRNA, Wnt / b-catenin, Hippo signaling, animal model, Therapeatic

Received: 14 May 2019; Accepted: 25 Oct 2019.

Copyright: © 2019 Gupta, Yadav, Rawat and Baranwal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Somesh Baranwal, Central University of Punjab, Bathinda, 151001, Punjab, India, someshbaranwal@gmail.com