T-Natural Killers and Interferon Gamma/Interleukin 4 in Augmentation of Infection in Foot Ulcer in Type 2 Diabetes

Overview

Journal Diabetes Metab Syndr Obes

Publisher Dove Medical Press

Specialty Endocrinology

Date 2021 May 7

PMID 33958881

Citations 8

Authors

Reham Hammad

Asmaa A Elmadbouly

Inass Hassan Ahmad

Shaymaa A Mohammed

Nehal Farouk

Zahraa Futooh

Mohamed Omar Alfy

Sarah Abozaid

Eman F Mohamed

Fatma M Kotb

Alzahra Abdelbadea

Nora Seliem

Ahmed ElShafei

Alya Mashaal

Affiliations

Soon will be listed here.

Abstract

Background: The link between immune system and type 2 diabetes mellitus (T2DM) pathogenesis attracted attention to demonstrate the role of immune cells and their secreted cytokines in T2DM development and its subsequent foot complications.

Objective: To investigate the relation between T Natural killer cell (TNK) %, Interleukin 4 (IL4) and Interferon gamma (IFN-γ) and diabetic foot infection (DFI) development in patients with diabetic foot ulcer (DFU).

Patients And Methods: Ninety patients with diabetes were included in this work, divided as T2DM group (n=30), DFU group (n=30), and DFI group (n=30). TNK% was detected using flow cytometry. Serum IL4 and IFN-γ were measured by ELISA. Diabetes biochemical parameters were also analyzed.

Results: Significant decrease was detected in TNK% and IFN-γ in DFI group compared to other 2 groups (<0.001). Significant decrease was detected in serum levels of IL4 in DFI group compared to T2DM group (=0.006). IFN-γ/IL4 was significantly decreased in DFI compared to DFU group (=0.020). There was a significant correlation of TNK% with both IL4 and IFN-γ (r=0.385, <0.001; r=0.534, <0.001, respectively). Significant negative correlation of TNK% with HbA1c and LDL was revealed (r=-0.631, <0.001; and r=-0.261, =0.013, respectively), while a positive correlation was seen with HDL (r=0.287, =0.006). A significant negative correlation of IL4 with HbA1c was found (r=-0.514, <0.001;. As for IFN-γ, a significant negative correlation with HbA1c and LDL was detected (r=-0.369, < 0.001; r=-0.229, =0.030). TNK % and IFN-γ level showed negative correlations with disease duration/year (r=-0.546, < 0.001; r=-0.338, =0.001,respectively).

Conclusion: Decline in TNK frequency has essential role in T2DM pathogenesis and subsequent foot complications. Downregulation of TNK% and IFN-γ level have potential roles in predicting infection of diabetic ulcer and are correlated with disease duration.

Citing Articles

Metabolic regulation of the immune system in health and diseases: mechanisms and interventions.

Hu T, Liu C, Lei M, Zeng Q, Li L, Tang H Signal Transduct Target Ther. 2024; 9(1):268.

PMID: 39379377 PMC: 11461632. DOI: 10.1038/s41392-024-01954-6.

Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers.

Yi W, Yuan Y, Bao Q, Zhao Z, Ding H, Song J J Inflamm Res. 2024; 17:3143-3157.

PMID: 38774446 PMC: 11107912. DOI: 10.2147/JIR.S452609.

Bioinformatics analysis identifies TGF-β signaling pathway-associated molecular subtypes and gene signature in diabetic foot.

Du G, Chen J, Zhu X, Zhu Z iScience. 2024; 27(3):109094.

PMID: 38439964 PMC: 10910239. DOI: 10.1016/j.isci.2024.109094.

Non-classical monocytes frequency and serum vitamin D levels are linked to diabetic foot ulcer associated with peripheral artery disease.

Hammad R, A Abdel Wahab M, Farouk N, Zakaria M, Eldosoky M, Elmadbouly A J Diabetes Investig. 2023; 14(10):1192-1201.

PMID: 37394883 PMC: 10512914. DOI: 10.1111/jdi.14048.

Type 2 Diabetes Mellitus- and Complication-Related Risk of Nontuberculous Mycobacterial Disease in a South Korean Cohort.

Jeon D, Kim S, Kim M, Chong Y, Shim T, Jung C Microbiol Spectr. 2023; :e0451122.

PMID: 36975830 PMC: 10100663. DOI: 10.1128/spectrum.04511-22.

References

Hammad R, El-Madbouly A, Kotb H, Zarad M . Frequency of Circulating B1a and B2 B-cell Subsets in Egyptian Patients with Type 2 Diabetes Mellitus. Egypt J Immunol. 2018; 25(1):71-80. View

Zamstein O, Sheiner E, Wainstock T, Landau D, Walfisch A . Maternal gestational diabetes and long-term respiratory related hospitalizations of the offspring. Diabetes Res Clin Pract. 2018; 140:200-207. DOI: 10.1016/j.diabres.2018.03.050. View

Hung J, Huang J, Yu A . Tailored design of NKT-stimulatory glycolipids for polarization of immune responses. J Biomed Sci. 2017; 24(1):22. PMC: 5364570. DOI: 10.1186/s12929-017-0325-0. View

Tsiavou A, Degiannis D, Hatziagelaki E, Koniavitou K, Raptis S . Intracellular IFN-gamma production and IL-12 serum levels in latent autoimmune diabetes of adults (LADA) and in type 2 diabetes. J Interferon Cytokine Res. 2004; 24(7):381-7. DOI: 10.1089/1079990041535665. View

Kivela J, Wikstrom K, Virtanen E, Georgoulis M, Cardon G, Civeira F . Obtaining evidence base for the development of Feel4Diabetes intervention to prevent type 2 diabetes - a narrative literature review. BMC Endocr Disord. 2020; 20(Suppl 1):140. PMC: 7066732. DOI: 10.1186/s12902-019-0468-y. View

Huang Z, Li S, Kou Y, Huang L, Yu T, Hu A . Risk factors for the recurrence of diabetic foot ulcers among diabetic patients: a meta-analysis. Int Wound J. 2019; 16(6):1373-1382. PMC: 7949075. DOI: 10.1111/iwj.13200. View

Schroder K, Hertzog P, Ravasi T, Hume D . Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2003; 75(2):163-89. DOI: 10.1189/jlb.0603252. View

Lipsky B, Senneville E, Abbas Z, Aragon-Sanchez J, Diggle M, Embil J . Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020; 36 Suppl 1:e3280. DOI: 10.1002/dmrr.3280. View

Kartika R, Purnamasari D, Pradipta S, Larasati R, Wibowo H . Impact of Low Interferon-γ and IL-10 Levels on TNF-α and IL-6 Production by PHA-Induced PBMCs in Type 2 Diabetes Mellitus. J Inflamm Res. 2020; 13:187-193. PMC: 7190380. DOI: 10.2147/JIR.S245064. View

10.

Chang Y, Ho K, Lu S, Huang C, Shiau M . Regulation of glucose/lipid metabolism and insulin sensitivity by interleukin-4. Int J Obes (Lond). 2011; 36(7):993-8. DOI: 10.1038/ijo.2011.168. View

11.

Sunandhakumari V, Sadasivan A, Koshi E, Krishna A, Alim A, Sebastian A . Effect of NonSurgical Periodontal Therapy on Plasma Levels of IL-17 in Chronic Periodontitis Patients with Well Controlled Type-II Diabetes Mellitus-A Clinical Study. Dent J (Basel). 2018; 6(2). PMC: 6023374. DOI: 10.3390/dj6020019. View

12.

. 2. Classification and Diagnosis of Diabetes: . Diabetes Care. 2019; 43(Suppl 1):S14-S31. DOI: 10.2337/dc20-S002. View

13.

Mahmoud M, Ghareeb D, Sahyoun H, Elshehawy A, Elsayed M . In Vivo Interrelationship between Insulin Resistance and Interferon Gamma Production: Protective and Therapeutic Effect of Berberine. Evid Based Complement Alternat Med. 2016; 2016:2039897. PMC: 5013203. DOI: 10.1155/2016/2039897. View

14.

Moura J, Madureira P, Leal E, Fonseca A, Carvalho E . Immune aging in diabetes and its implications in wound healing. Clin Immunol. 2019; 200:43-54. PMC: 7322932. DOI: 10.1016/j.clim.2019.02.002. View

15.

Foss-Freitas M, Foss N, Donadi E, Foss M . Effect of metabolic control on interferon-gamma and interleukin-10 production by peripheral blood mononuclear cells from type 1 and type 2 diabetic patients. Braz J Med Biol Res. 2007; 40(5):671-7. DOI: 10.1590/s0100-879x2007000500010. View

16.

Van Kaer L, Wu L . Therapeutic Potential of Invariant Natural Killer T Cells in Autoimmunity. Front Immunol. 2018; 9:519. PMC: 5859017. DOI: 10.3389/fimmu.2018.00519. View

17.

Lv X, Gao Y, Dong T, Yang L . Role of Natural Killer T (NKT) Cells in Type II Diabetes-Induced Vascular Injuries. Med Sci Monit. 2018; 24:8322-8332. PMC: 6256848. DOI: 10.12659/MSM.912446. View

18.

Gomez-Diaz R, Aguilar M, Meguro E, Marquez R, Magana E, Carmen Martinez-Garcia M . The role of natural killer T (NKT) cells in the pathogenesis of type 1 diabetes. Curr Diabetes Rev. 2011; 7(4):278-83. DOI: 10.2174/157339911796397839. View

19.

East J, Kennedy A, Webb T . Raising the roof: the preferential pharmacological stimulation of Th1 and th2 responses mediated by NKT cells. Med Res Rev. 2012; 34(1):45-76. PMC: 4102678. DOI: 10.1002/med.21276. View

20.

Zhang Y, Lazzarini P, McPhail S, van Netten J, Armstrong D, Pacella R . Global Disability Burdens of Diabetes-Related Lower-Extremity Complications in 1990 and 2016. Diabetes Care. 2020; 43(5):964-974. DOI: 10.2337/dc19-1614. View