Interleukin-25-Mediated-IL-17RB Upregulation Promotes Cutaneous Wound Healing in Diabetic Mice by Improving Endothelial Cell Functions

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Feb 7

PMID 35126394

Authors

Fang Zhang

Ye Liu

Shiqi Wang

Xin Yan

Yue Lin

Deyan Chen

Qian Tan

Zhiwei Wu

Affiliations

Soon will be listed here.

Abstract

Diabetic foot ulcer (DFU) frequently leads to non-traumatic amputation and finally even death. However, the mechanism of DFU is not fully understood. Interleukin 25 (IL-25), an alarmin cytokine that responds to tissue injury, has been reported to participate in tissue regeneration and maintaining glucose homeostasis. However, the role of IL-25 in diabetic wound healing remains unknown. Here, we showed that interleukin 17 receptor B (IL-17RB), the functional receptor of IL-25, was significantly inhibited in the wound skin of both diabetic patients with DFU and streptozotocin (STZ)-induced diabetic mice. Topical administration of recombinant IL-25 protein improved angiogenesis and collagen deposition in the wound bed and thus ameliorated delayed diabetic wound healing. IL-25 increased endothelial-specific CD31 expression in diabetic wounds and exogenous IL-25 protected endothelial cells from high glucose-impaired cell migration and tube formation . We further revealed that IL-25-mediated-IL-17RB signaling rescued the downregulation of Wnt/β-catenin pathway both in diabetic mice and in HUVECs and induced the phosphorylation of AKT and ERK 1/2 in HUVECs under high glucose conditions. This study defines a positive regulatory role of IL-25-mediated-IL-17RB signaling in diabetic wound healing and suggests that induction of IL-25-mediated-IL-17RB signaling may be a novel therapeutic strategy for treating poor healing diabetic wounds.

Citing Articles

Wound management, healing, and early prosthetic rehabilitation: Part 2 - A scoping review of physical biomarkers.

Williams-Reid H, Johannesson A, Buis A Can Prosthet Orthot J. 2025; 7(2):43716.

PMID: 39990247 PMC: 11844764. DOI: 10.33137/cpoj.v7i2.43716.

Wound management, healing, and early prosthetic rehabilitation: Part 1 - A scoping review of healing and non-healing definitions.

Williams-Reid H, Johannesson A, Buis A Can Prosthet Orthot J. 2025; 7(2):43715.

PMID: 39990241 PMC: 11844765. DOI: 10.33137/cpoj.v7i2.43715.

Machine learning-driven discovery of novel therapeutic targets in diabetic foot ulcers.

Yu X, Wu Z, Zhang N Mol Med. 2024; 30(1):215.

PMID: 39543487 PMC: 11562697. DOI: 10.1186/s10020-024-00955-z.

Trained immunity of intestinal tuft cells during infancy enhances host defense against enteroviral infections in mice.

Chen D, Wu J, Zhang F, Lyu R, You Q, Qian Y EMBO Mol Med. 2024; 16(10):2516-2538.

PMID: 39261649 PMC: 11479266. DOI: 10.1038/s44321-024-00128-9.

Preparation of Luvangetin Nanoemulsions: Antimicrobial Mechanism and Role in Infected Wound Healing.

Chong Y, Yu D, Han R, Li Y, Gu Y, Lu Z Int J Nanomedicine. 2024; 19:5493-5509.

PMID: 38882542 PMC: 11178095. DOI: 10.2147/IJN.S457322.

References

Hams E, Locksley R, McKenzie A, Fallon P . Cutting edge: IL-25 elicits innate lymphoid type 2 and type II NKT cells that regulate obesity in mice. J Immunol. 2013; 191(11):5349-53. PMC: 3847854. DOI: 10.4049/jimmunol.1301176. View

Gregory L, Jones C, Walker S, Sawant D, Gowers K, Campbell G . IL-25 drives remodelling in allergic airways disease induced by house dust mite. Thorax. 2012; 68(1):82-90. PMC: 3534261. DOI: 10.1136/thoraxjnl-2012-202003. View

Gurtner G, Werner S, Barrandon Y, Longaker M . Wound repair and regeneration. Nature. 2008; 453(7193):314-21. DOI: 10.1038/nature07039. View

Galkowska H, Wojewodzka U, Olszewski W . Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair Regen. 2006; 14(5):558-65. DOI: 10.1111/j.1743-6109.2006.00155.x. View

Chen X, Duong M, Psaltis P, Bursill C, Nicholls S . High-density lipoproteins attenuate high glucose-impaired endothelial cell signaling and functions: potential implications for improved vascular repair in diabetes. Cardiovasc Diabetol. 2017; 16(1):121. PMC: 5622442. DOI: 10.1186/s12933-017-0605-8. View

Ding Q, Xia W, Liu J, Yang J, Lee D, Xia J . Erk associates with and primes GSK-3beta for its inactivation resulting in upregulation of beta-catenin. Mol Cell. 2005; 19(2):159-70. DOI: 10.1016/j.molcel.2005.06.009. View

Quattrini C, Jeziorska M, Boulton A, Malik R . Reduced vascular endothelial growth factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care. 2007; 31(1):140-5. DOI: 10.2337/dc07-1556. View

Everett E, Mathioudakis N . Update on management of diabetic foot ulcers. Ann N Y Acad Sci. 2018; 1411(1):153-165. PMC: 5793889. DOI: 10.1111/nyas.13569. View

Vagesjo E, Ohnstedt E, Mortier A, Lofton H, Huss F, Proost P . Accelerated wound healing in mice by on-site production and delivery of CXCL12 by transformed lactic acid bacteria. Proc Natl Acad Sci U S A. 2018; 115(8):1895-1900. PMC: 5828606. DOI: 10.1073/pnas.1716580115. View

10.

Shi Y, Shu B, Yang R, Xu Y, Xing B, Liu J . Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately. Stem Cell Res Ther. 2015; 6:120. PMC: 4501079. DOI: 10.1186/s13287-015-0103-4. View

11.

Gay D, Kwon O, Zhang Z, Spata M, Plikus M, Holler P . Fgf9 from dermal γδ T cells induces hair follicle neogenesis after wounding. Nat Med. 2013; 19(7):916-23. PMC: 4054871. DOI: 10.1038/nm.3181. View

12.

Lin F, Yang Y, Wei S, Huang X, Peng Z, Ke X . Hydrogen Sulfide Protects Against High Glucose-Induced Human Umbilical Vein Endothelial Cell Injury Through Activating PI3K/Akt/eNOS Pathway. Drug Des Devel Ther. 2020; 14:621-633. PMC: 7027865. DOI: 10.2147/DDDT.S242521. View

13.

Jere S, Houreld N, Abrahamse H . Role of the PI3K/AKT (mTOR and GSK3β) signalling pathway and photobiomodulation in diabetic wound healing. Cytokine Growth Factor Rev. 2019; 50:52-59. DOI: 10.1016/j.cytogfr.2019.03.001. View

14.

Huang X, Liang P, Jiang B, Zhang P, Yu W, Duan M . Hyperbaric oxygen potentiates diabetic wound healing by promoting fibroblast cell proliferation and endothelial cell angiogenesis. Life Sci. 2020; 259:118246. DOI: 10.1016/j.lfs.2020.118246. View

15.

Feng J, Li L, Ou Z, Li Q, Gong B, Zhao Z . IL-25 stimulates M2 macrophage polarization and thereby promotes mitochondrial respiratory capacity and lipolysis in adipose tissues against obesity. Cell Mol Immunol. 2017; 15(5):493-505. PMC: 6068125. DOI: 10.1038/cmi.2016.71. View

16.

Davis F, Kimball A, Boniakowski A, Gallagher K . Dysfunctional Wound Healing in Diabetic Foot Ulcers: New Crossroads. Curr Diab Rep. 2018; 18(1):2. DOI: 10.1007/s11892-018-0970-z. View

17.

Hart T, Milner R, Cifu A . Management of a Diabetic Foot. JAMA. 2017; 318(14):1387-1388. DOI: 10.1001/jama.2017.11700. View

18.

Armstrong D, Boulton A, Bus S . Diabetic Foot Ulcers and Their Recurrence. N Engl J Med. 2017; 376(24):2367-2375. DOI: 10.1056/NEJMra1615439. View

19.

Klein K, Buse J . The trials and tribulations of determining HbA targets for diabetes mellitus. Nat Rev Endocrinol. 2020; 16(12):717-730. PMC: 11653296. DOI: 10.1038/s41574-020-00425-6. View

20.

Mitchell P, OByrne P . Biologics and the lung: TSLP and other epithelial cell-derived cytokines in asthma. Pharmacol Ther. 2016; 169:104-112. DOI: 10.1016/j.pharmthera.2016.06.009. View