Exploring the Mechanism of Oral Mucosal Immune Homeostasis Based on the IL-37 Signaling Pathway
CHEN Yu1, DONG Weiwei1, ZHAO Yu2, JIN He1
1. Dental Department, Mingji Hospital Affiliated to Nanjing Medical University, NanJing 210000, China;
2. Department of Anesthesiology, Lu’an Shili Hospital, Lu’an 237000, China
Abstract：Objective This study aims to elucidate the mechanism behind oral mucosal immune homeostasis by investigating the IL-37 signaling pathway. Methods An experimental model of oral inflammation was established in C57BL/6J mice through gingival nematode infection and induction of oral inflammation by human macrophages. The mice were categorized into control and rhIL-37b treatment groups. IL-37, inflammatory cytokines (IL-6, TNF-α, IL-10, IL-1β), and the NF-κB pathway were assessed using qPCR. Western blotting was employed to analyze the protein expression of IL-37 and the NF-κB pathway. Micro-computed tomography (microCT) imaging was utilized to quantify bone loss. Results Following gingival nematode infection, THP-1 cells exhibited elevated IL-37 mRNA expression. In human macrophages treated with rhIL-37b, production of IL-6, TNF-α, and IL-1β was reduced, accompanied by enhanced degradation of IκBα and diminished levels of phosphorylated p65 after gingival nematode infection, as compared to the control group. In the mouse periodontitis model, the rhIL-37b-treated group demonstrated a significant reduction in gingival inflammation and bone loss. Conclusion IL-37 plays a regulatory role in the inflammatory cytokine response of periodontitis by inhibiting the NF-κB signaling pathway. Consequently, IL-37 contributes to the mitigation of gingival tissue bone loss and cytokine expression.
[1] Kwon T, Lamster IB, Levin L.Current Concepts in the Management of Periodontitis[J]. Int Dent J, 2021, 71(6) : 462-476.
[2] Baeza M, Morales A, Cisterna C, et al.Effect of periodontal treatment in patients with periodontitis and diabetes: systematic review and meta-analysis[J]. J Appl Oral Sci, 2020, 28: e20190248.
[3] Zhang X, Zhang S, Yan X, et al.m6A regulator-mediated RNA methylation modification patterns are involved in immune microenvironment regulation of periodontitis[J]. J Cell Mol Med, 2021, 25(7) : 3634-3645.
[4] Hajishengallis G, Korostoff JM.Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later[J]. Periodontol 2000, 2017, 75(1) : 116-151.
[5] Papathanasiou E, Conti P, Carinci F, et al.IL-1 Superfamily Members and Periodontal Diseases[J]. J Dent Res, 2020, 99(13) : 1425-1434.
[6] Sánchez-Fernández A, Zandee S, Amo-Aparicio J, et al.IL-37 exerts therapeutic effects in experimental autoimmune encephalomyelitis through the receptor complex IL-1R5/IL-1R8[J]. Theranostics, 2021, 11(1) : 1-13.
[7] Zhou P, Li Q, Su S, et al.Interleukin 37 Suppresses M1 Macrophage Polarization Through Inhibition of the Notch1 and Nuclear Factor Kappa B Pathways[J]. Front Cell Dev Biol, 2020, 8: 56.
[8] Komlós G, Csurgay K, Horváth F, et al.Periodontitis as a risk for oral cancer: a case-control study[J]. BMC Oral Health, 2021, 21(1) : 640.
[9] Nwizu N, Wactawski-Wende J, Genco RJ.Periodontal disease and cancer: Epidemiologic studies and possible mechanisms[J]. Periodontol 2000, 2020, 83(1) : 213-233.
[10] Su Z, Tao X.Current Understanding of IL-37 in Human Health and Disease[J]. Front Immunol, 2021, 12: 696605.
[11] Mei Y, Liu H.IL-37: An anti-inflammatory cytokine with antitumor functions[J]. Cancer Rep (Hoboken) , 2019, 2(2) : e1151.
[12] Rai V, Radwan MM, Agrawal DK. IL-33, IL-37,Vitamin D Interaction Mediate Immunomodulation of Inflammation in Degenerating Cartilage[J]. Antibodies (Basel) , 2021, 26, 10(4) : 41.
[13] Feng M, Kang M, He F, et al.Plasma interleukin-37 is increased and inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells in systemic juvenile idiopathic arthritis patients[J]. J Transl Med, 2018, 16(1) : 277.
[14] Chen Y, Wang H, Yang Q, et al.Single-cell RNA landscape of the osteoimmunology microenvironment in periodontitis[J]. Theranostics, 2022, 12(3) : 1074-1096.
[15] Yue Y, Liu X, Li Y, et al.The role of TLR4/MyD88/NF-κB pathway in periodontitis-induced liver inflammation of rats[J]. Oral Dis, 2021, 27(4) : 1012-1021.
[16] Araújo AA, Pereira ASBF, Medeiros CACX, et al.Effects of metformin on inflammation, oxidative stress, and bone loss in a rat model of periodontitis[J]. PLoS One, 2017, 12(8) : e0183506.
[17] Du Y, Wang X, Jiao Y, et al.Importin 8 is involved in human periodontitis by the NF-κB pathway[J]. Int J Clin Exp Pathol, 2019, 12(3) : 711-716.
[18] Dhingra K, Vandana KL.Indices for measuring periodontitis: a literature review[J]. Int Dent J, 2011, 61(2) : 76-84.
2023, Vol. 20 
