IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

Kong, Dejun; Hu, Yonghao; Li, Xiang; Yu, Dingding; Li, Hongyue; Zhao, Yiming; Qin, Yafei; Wang, Jin; Zhang, Baoren; Wang, Bo; Wang, Hongda; Li, Guangming; Wang, Hao

doi:10.21203/rs.2.23662/v1

Cited by 4 publications

(8 citation statements)

References 33 publications

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Section: Effects On Mesenchymal Stem Cells By Il-37mentioning

confidence: 99%

“…IL-37 gene-modified MSCs (IL-37-MSCs) can distinctly inhibit intestinal ischemia reperfusion injury (IRI) by migrating to the damaged tissue (47). Indeed, the treatment with IL-37-MSCs on IRI rats strengthens gut barrier function and reduced the local and systemic level of the inflammatory cytokine IL-1b, as compared with rats treated with MSCs or recombinant IL-37 (47). In addition, IL-37-MSCs treatment in IRI rats significantly decreases tissue damage due to NLRP3, the downstream targets such as cleaved caspase-1, IL-1b, and IL-18, and IL-1b-and IL-18-related proinflammatory mediators IL-6 and TNF-a mRNA expression, suggesting that NLRP3-related signaling pathway could be associated to the protection mediated by IL-37-MSC (47).…”

Section: Effects On Mesenchymal Stem Cells By Il-37mentioning

confidence: 99%

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Current Understanding of IL-37 in Human Health and Disease

Tao

2021

Front. Immunol.

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IL-37 is a recently discovered cytokine in the IL-1 family exerting broad protective effects on inflammatory diseases, autoimmune diseases, and cancer. Immune and non-immune cells produce the IL-37 precursor upon pro-inflammatory stimuli. Intracellularly, caspase-1 cleaves and activates IL-37, and its mature form binds to Smad3; this complex translocates into the nucleus where it suppresses cytokine production, consequently reducing inflammation. Extracellularly, IL-37 forms a complex with IL-18Rα and IL-1R8 (formerly TIR8 or SIGIRR) that transduces anti-inflammatory signals by the suppression of NF-κB and MAPK and the activation of Mer-PTEN-DOK pathways. During inflammation, IL-37 suppresses the expression of several pro-inflammatory cytokine in favor to the expression of the anti-inflammatory ones by the regulation of macrophage polarization, lipid metabolism, inflammasome function, TSLP synthesis and miRNAs function. Moreover, IL-37 not only regulates the innate and acquired immunity, but also improves aging-associated immunosenescence. Furthermore, IL-37 exerts an inhibitory effect on tumor angiogenesis and metastasis, and progression. Finally, IL-37 may have a potential ability to reduce excessive inflammation since it is aberrantly expressed in patients with inflammatory diseases, autoimmune diseases, and cancer, thus, it may be used as a marker for different types of diseases. Therefore, this review provides an updated view of the role of IL-37 in human health and disease, and discusses the potential of IL-37 as a therapeutic target and biomarker in inflammatory diseases, autoimmune diseases, and cancer.

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Section: Effects On Mesenchymal Stem Cells By Il-37mentioning

confidence: 99%

Section: Effects On Mesenchymal Stem Cells By Il-37mentioning

confidence: 99%

Current Understanding of IL-37 in Human Health and Disease

Tao

2021

Front. Immunol.

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“…After title and abstract screening, 25 articles were identified and underwent review of the full text. Ultimately, 7 studies were included in the meta-analysis [4,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] (Fig. 1).…”

Section: Study Screenmentioning

confidence: 99%

“…MSCs release many types of cytokines factors through paracrine effects or directly interacts with immune cells, leading to immunomodulation. The included studies showed that MSCs positively contributed to recovery process by decreasing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, TGF-β1, MPO, NF-κB, and iNOS) [4,18,21,23,26,27,29] and increasing anti-inflammatory cytokines (EP3 and IL-1Ra) [18] following IRI in the intestine of animals. The Toll/Interleukin-1 receptor (TIR) domain is highly conserved among all toll-like receptors (TLRs) and triggers the TLR-mediated signaling pathways.…”

Section: Protective Effect Of Mscs Related To Inflammationmentioning

confidence: 99%

Mesenchymal stem cells against intestinal ischemia–reperfusion injury: a systematic review and meta-analysis of preclinical studies

et al. 2022

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Background Intestinal ischemia–reperfusion injury (IRI) causes localized and distant tissue lesions. Multiple organ failure is a common complication of severe intestinal IRI, leading to its high rates of morbidity and mortality. Thus far, this is poorly treated, and there is an urgent need for new more efficacious treatments. This study evaluated the beneficial effects of mesenchymal stem cells (MSCs) therapy on intestinal IRI using many animal experiments. Methods We conducted a comprehensive literature search from 4 databases: Pubmed, Embase, Cochrane library, and Web of science. Primary outcomes included the survival rate, Chiu’s score, intestinal levels of IL-6, TNF-α and MDA, as well as serum levels of DAO, D-Lactate, and TNF-α. Statistical analysis was carried out using Review Manager 5.3. Results It included Eighteen eligible researches in the final analysis. We demonstrated that survival rates in animals following intestinal IRI were higher with MSCs treatment compared to vehicle treatment. Besides, MSCs treatment attenuated intestinal injury caused by IRI, characterized by lower Chiu’s score (− 1.96, 95% CI − 2.72 to − 1.19, P < 0.00001), less intestinal inflammation (IL-6 (− 2.73, 95% CI − 4.19 to − 1.27, P = 0.0002), TNF-α (− 3.00, 95% CI − 4.74 to − 1.26, P = 0.0007)) and oxidative stress (MDA (− 2.18, 95% CI − 3.17 to − 1.19, P < 0.0001)), and decreased serum levels of DAO (− 1.39, 95% CI − 2.07 to − 0.72, P < 0.0001), D-Lactate (− 1.54, 95% CI − 2.18 to − 0.90, P < 0.00001) and TNF-α (− 2.42, 95% CI − 3.45 to − 1.40, P < 0.00001). The possible mechanism for MSCs to treat intestinal IRI might be through reducing inflammation, alleviating oxidative stress, as well as inhibiting the apoptosis and pyroptosis of the intestinal epithelial cells. Conclusions Taken together, these studies revealed that MSCs as a promising new treatment for intestinal IRI, and the mechanism of which may be associated with inflammation, oxidative stress, apoptosis, and pyroptosis. However, further studies will be required to confirm these findings.

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“…It has been demonstrated that the transgenic mice expressing human IL-37 gene can protect them from different pro-inflammatory situations, such as ulcerative colitis (UC) [40] and LPS-induced endotoxemia [38]. Moreover, we and others have reported that IL-37 has synergistic effects with MSCs or ERCs in attenuation of UC [41], intestinal ischemia-reperfusion injury [42], concanavalin A-induced hepatitis [43], and SLE [44] via different mechanisms. Recently, our ongoing study has also demonstrated the effects of recombinant IL-37 in inhibition of acute cardiac allograft rejection.…”

Section: Introductionmentioning

confidence: 99%

IL-37 overexpression promotes endometrial regenerative cell-mediated inhibition of cardiac allograft rejection

et al. 2022

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Background Endometrial regenerative cells (ERCs) play an important role in attenuation of acute allograft rejection, while their effects are limited. IL-37, a newly discovered immunoregulatory cytokine of the IL-1 family, can regulate both innate and adaptive immunity. Whether IL-37 overexpression can enhance the therapeutic effects of ERCs in inhibition of acute cardiac allograft rejection remains unknown and will be explored in this study. Methods C57BL/6 mice recipients receiving BALB/c mouse heterotopic heart allografts were randomly divided into the phosphate-buffered saline (untreated), ERC treated, negative lentiviral control ERC (NC-ERC) treated, and IL-37 overexpressing ERC (IL-37-ERC) treated groups. Graft pathological changes were assessed by H&E staining. The intra-graft cell infiltration and splenic immune cell populations were analyzed by immunohistochemistry and flow cytometry, respectively. The stimulatory property of recipient DCs was tested by an MLR assay. Furthermore, serum cytokine profiles of recipients were measured by ELISA assay. Results Mice treated with IL-37-ERCs achieved significantly prolonged allograft survival compared with the ERC-treated group. Compared with all the other control groups, IL-37-ERC-treated group showed mitigated inflammatory response, a significant increase in tolerogenic dendritic cells (Tol-DCs), regulatory T cells (Tregs) in the grafts and spleens, while a reduction of Th1 and Th17 cell population. Additionally, there was a significant upregulation of immunoregulatory IL-10, while a reduction of IFN-γ, IL-17A, IL-12 was detected in the sera of IL-37-ERC-treated recipients. Conclusion IL-37 overexpression can promote the therapeutic effects of ERCs to inhibit acute allograft rejection and further prolong graft survival. This study suggests that gene-modified ERCs overexpressing IL-37 may pave the way for novel therapeutic options in the field of transplantation.

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IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

Cited by 4 publications

References 33 publications

Current Understanding of IL-37 in Human Health and Disease

Current Understanding of IL-37 in Human Health and Disease

Mesenchymal stem cells against intestinal ischemia–reperfusion injury: a systematic review and meta-analysis of preclinical studies

IL-37 overexpression promotes endometrial regenerative cell-mediated inhibition of cardiac allograft rejection

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