中性粒细胞与牙周炎关系的研究进展

doi:10.13591/j.cnki.kqyx.2024.04.010

摘要/Abstract

摘要：

牙周炎是一种常见的口腔慢性炎症,宿主因素是其致病机制之一。作为数目最多的免疫细胞,中性粒细胞可影响牙周免疫稳态,其数量或功能改变可通过多种机制加重牙周炎症,基于中性粒细胞的牙周炎干预措施在动物实验中展现出较好的牙周炎治疗前景。本文综述了中性粒细胞在牙周炎中作用的研究进展,并总结展望目前靶向中性粒细胞的治疗手段,以期为牙周炎防治提供新的视角。

关键词: 中性粒细胞, 牙周炎, 免疫治疗

Abstract:

Periodontitis is a prevalent and persisting oral inflammation, during which host factors are critically involved. As the most abundant immune cells, neutrophils actively partake in periodontal homeostasis, the alteration of neutrophil number or function could aggravate periodontitis through multifaceted mechanisms. Additionally, neutrophil-targeted therapies showed promising effects on treating periodontitis in animal trials. In this paper, research progress of neutrophil’s role in periodontitis and immunomodulation on neutrophil were reviewed in order to provide new perspectives for periodontitis treatment.

Key words: neutrophil, periodontitis, neutrophil-modulating treatment

中图分类号:

R781.4

王雪奎, 孙瑶. 中性粒细胞与牙周炎关系的研究进展[J]. 口腔医学, 2024, 44(4): 292-296.

WANG Xuekui, SUN Yao. Role of neutrophil in periodontitis: An updated review[J]. Stomatology, 2024, 44(4): 292-296.

图/表 1

表1

参考文献 43

[1]	Jiao J, Jing WD, Si Y, et al. The prevalence and severity of periodontal disease in Mainland China: Data from the Fourth National Oral Health Survey (2015—2016)[J]. J Clin Periodontol, 2021, 48(2):168-179. doi: 10.1111/jcpe.v48.2
[2]	Wallis RS, O’Garra A, Sher A, et al. Host-directed immunotherapy of viral and bacterial infections: Past, present and future[J]. Nat Rev Immunol, 2023, 23(2):121-133. doi: 10.1038/s41577-022-00734-z
[3]	Li XF, Wang H, Yu X, et al. Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities[J]. Cell, 2022, 185(10):1709-1727.e18. doi: 10.1016/j.cell.2022.03.043 pmid: 35483374
[4]	Silva LM, Doyle AD, Greenwell-Wild T, et al. Fibrin is a critical regulator of neutrophil effector function at the oral mucosal barrier[J]. Science, 2021, 374(6575):eabl5450. doi: 10.1126/science.abl5450
[5]	Williams DW, Greenwell-Wild T, Brenchley L, et al. Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity[J]. Cell, 2021, 184(15):4090-4104.e15. doi: 10.1016/j.cell.2021.05.013 pmid: 34129837
[6]	Moutsopoulos NM, Lionakis MS, Hajishengallis G. Inborn errors in immunity: Unique natural models to dissect oral immunity[J]. J Dent Res, 2015, 94(6):753-758. doi: 10.1177/0022034515583533 pmid: 25900229
[7]	Dutzan N, Kajikawa T, Abusleme L, et al. A dysbiotic microbiome triggers T_H17 cells to mediate oral mucosal immunopathology in mice and humans[J]. Sci Transl Med, 2018, 10(463):eaat0797. doi: 10.1126/scitranslmed.aat0797
[8]	谢春雨, 许子悦, 刘好好, 等. 中性粒细胞在牙周炎疾病中作用的研究进展[J]. 现代免疫学, 2017, 37(2):157-160.
[9]	周侨, 孙颖. 中性粒细胞在牙周炎发生发展中的作用的研究进展[J]. 口腔医学, 2016, 36(6):556-560.
[10]	Bianchi M, Hakkim A, Brinkmann V, et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis[J]. Blood, 2009, 114(13):2619-2622. doi: 10.1182/blood-2009-05-221606 pmid: 19541821
[11]	Stroobant J, Harris MC, Cody CS, et al. Diminished bactericidal capacity for group B streptococci of neutrophils from children with chronic granulomatous disease[J]. Infect Immun, 1983, 39(2):966-969. doi: 10.1128/iai.39.2.966-969.1983 pmid: 6339394
[12]	Ye Y, Carlsson G, Wondimu B, et al. Mutations in the ELANE gene are associated with development of periodontitis in patients with severe congenital neutropenia[J]. J Clin Immunol, 2011, 31(6):936-945. doi: 10.1007/s10875-011-9572-0 pmid: 21796505
[13]	Keszei M, Record J, Kritikou JS, et al. Constitutive activation of WASp in X-linked neutropenia renders neutrophils hyperactive[J]. J Clin Invest, 2021, 131(23):e156513. doi: 10.1172/JCI156513
[14]	Lafon A, Faivre L, Seux D, et al. Periodontal disorders in a cohort of patients with Cohen syndrome[J]. Spec Care Dentist, 2021, 41(1):118-124. doi: 10.1111/scd.12544 pmid: 33202072
[15]	Sharma P, Nicoli ER, Serra-Vinardell J, et al. Chediak-Higashi syndrome: A review of the past, present, and future[J]. Drug Discov Today Dis Models, 2020, 31:31-36. doi: 10.1016/j.ddmod.2019.10.008
[16]	Hajishengallis G, Moutsopoulos NM. Etiology of leukocyte adhesion deficiency-associated periodontitis revisited: Not a raging infection but a raging inflammatory response[J]. Expert Rev Clin Immunol, 2014, 10(8):973-975. doi: 10.1586/1744666X.2014.929944
[17]	Tahata S, Raymond K, Quade M, et al. Defining the mild variant of leukocyte adhesion deficiency type Ⅱ (SLC35C1-congenital disorder of glycosylation) and response to l-fucose therapy: Insights from two new families and review of the literature[J]. Am J Med Genet A, 2022, 188(7):2005-2018. doi: 10.1002/ajmg.a.v188.7
[18]	Kuhns DB, Fink DL, Choi U, et al. Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency[J]. Blood, 2016, 128(17):2135-2143. pmid: 27557945
[19]	Giannetti L, Apponi R, Dello Diago AM, et al. Papillon-Lefèvre syndrome: Oral aspects and treatment[J]. Dermatol Ther, 2020, 33(3):e13336.
[20]	Newman MG. Newman and carranza’s clinical periodontology[M]. Hdlend: Elservier Health Science, 2019.
[21]	Fine N, Hassanpour S, Borenstein A, et al. Distinct oral neutrophil subsets define health and periodontal disease states[J]. J Dent Res, 2016, 95(8):931-938. doi: 10.1177/0022034516645564 pmid: 27270666
[22]	Nicu EA, Loos BG. Polymorphonuclear neutrophils in periodontitis and their possible modulation as a therapeutic approach[J]. Periodontol 2000, 2016, 71(1):140-163. doi: 10.1111/prd.2016.71.issue-1
[23]	Gustafsson A, Ito H, Asman B, et al. Hyper-reactive mononuclear cells and neutrophils in chronic periodontitis[J]. J Clin Periodontol, 2006, 33(2):126-129. pmid: 16441737
[24]	Geng S, Zhang Y, Lee C, et al. Novel reprogramming of neutrophils modulates inflammation resolution during atherosclerosis[J]. Sci Adv, 2019, 5(2):eaav2309. doi: 10.1126/sciadv.aav2309
[25]	Hamam HJ, Khan MA, Palaniyar N. Histone acetylation promotes neutrophil extracellular trap formation[J]. Biomolecules, 2019, 9(1):32. doi: 10.3390/biom9010032
[26]	Hernández M, Gamonal J, Tervahartiala T, et al. Associations between matrix metalloproteinase-8 and-14 and myeloperoxidase in gingival crevicular fluid from subjects with progressive chronic periodontitis: A longitudinal study[J]. J Periodontol, 2010, 81(11):1644-1652. doi: 10.1902/jop.2010.100196 pmid: 20653434
[27]	Wei ZK, Wang JJ, Wang YN, et al. Effects of neutrophil extracellular traps on bovine mammary epithelial cells in vitro[J]. Front Immunol, 2019, 10:1003. doi: 10.3389/fimmu.2019.01003
[28]	White PC, Chicca IJ, Cooper PR, et al. Neutrophil extracellular traps in periodontitis: A web of intrigue[J]. J Dent Res, 2016, 95(1):26-34. doi: 10.1177/0022034515609097 pmid: 26442948
[29]	Kim TS, Silva LM, Theofilou VI, et al. Neutrophil extracellular traps and extracellular histones potentiate IL-17 inflammation in periodontitis[J]. J Exp Med, 2023, 220(9):e20221751. doi: 10.1084/jem.20221751
[30]	Chakravarti A, Raquil MA, Tessier P, et al. Surface RANKL of Toll-like receptor 4-stimulated human neutrophils activates osteoclastic bone resorption[J]. Blood, 2009, 114(8):1633-1644. doi: 10.1182/blood-2008-09-178301 pmid: 19546479
[31]	Ozuna H, Uriarte SM, Demuth DR. The hunger games: Aggregatibacter actinomycetemcomitans exploits human neutrophils as an epinephrine source for survival[J]. Front Immunol, 2021, 12:707096. doi: 10.3389/fimmu.2021.707096
[32]	Hiyoshi T, Domon H, Maekawa T, et al. Aggregatibacter actinomycetemcomitans induces detachment and death of human gingival epithelial cells and fibroblasts via elastase release following leukotoxin-dependent neutrophil lysis[J]. Microbiol Immunol, 2019, 63(3/4):100-110. doi: 10.1111/mim.v63.3-4
[33]	Maekawa T, Krauss JL, Abe T, et al. Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis[J]. Cell Host Microbe, 2014, 15(6):768-778. doi: 10.1016/j.chom.2014.05.012 pmid: 24922578
[34]	Tözüm TF, Berker E, Ersoy F, et al. The relationship between periodontal status and peripheral levels of neutrophils in two consanguineous siblings with severe congenital neutropenia: Case reports[J]. Quintessence Int, 2003, 34(3):221-226. pmid: 12731605
[35]	Goultschin J, Attal U, Goldstein M, et al. The relationship between peripheral levels of leukocytes and neutrophils and periodontal disease status in a patient with congenital neutropenia[J]. J Periodontol, 2000, 71(9):1499-1505. pmid: 11022781
[36]	Maekawa T, Briones RA, Resuello RRG, et al. Inhibition of pre-existing natural periodontitis in non-human Primates by a locally administered peptide inhibitor of complement C3[J]. J Clin Periodontol, 2016, 43(3):238-249. doi: 10.1111/jcpe.12507 pmid: 26728318
[37]	Hasturk H, Hajishengallis G, Forsyth Institute Center for Clinical and Translational Research staff, et al. Phase Ⅱa clinical trial of complement C3 inhibitor AMY-101 in adults with periodontal inflammation[J]. J Clin Invest, 2021, 131(23):e152973. doi: 10.1172/JCI152973
[38]	Shin J, Maekawa T, Abe T, et al. DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman Primates[J]. Sci Transl Med, 2015, 7(307):307ra155.
[39]	Liu YD, Carmona-Rivera C, Moore E, et al. Myeloid-specific deletion of peptidylarginine deiminase 4 mitigates atherosclerosis[J]. Front Immunol, 2018, 9:1680. doi: 10.3389/fimmu.2018.01680 pmid: 30140264
[40]	Caton J, Ryan ME. Clinical studies on the management of periodontal diseases utilizing subantimicrobial dose doxycycline (SDD)[J]. Pharmacol Res, 2011, 63(2):114-120. doi: 10.1016/j.phrs.2010.12.003 pmid: 21182947
[41]	Bamashmous S, Kotsakis GA, Kerns KA, et al. Human variation in gingival inflammation[J]. Proc Natl Acad Sci USA, 2021, 118(27):e2012578118.
[42]	Nicu EA, Van der Velden U, Everts V, et al. Hyper-reactive PMNs in FcgammaRⅡa 131 H/H genotype periodontitis patients[J]. J Clin Periodontol, 2007, 34(11):938-945. pmid: 17877745
[43]	Shinjo T, Onizuka S, Zaitsu Y, et al. Dysregulation of CXCL1 expression and neutrophil recruitment in insulin resistance and diabetes-related periodontitis in male mice[J]. Diabetes, 2023, 72(7):986-998. doi: 10.2337/db22-1014 pmid: 37058471

疾病/综合征	基因	中性粒细胞的改变	牙周临床表现
周期性中性粒细胞减少和严重先天性中性粒蛋白减少症	ELANE	突变基因对应的蛋白及中性粒细胞改	糜烂性、出血性、疼痛性牙龈炎和牙周炎^[12]
X连锁中性粒细胞减少症	WAS	肌动蛋白调节因子,功能获得性突变,关键WASp蛋白293位点氨基酸的持续性磷酸化,表现为髓系细胞分化受阻,中性粒细胞激活	症状不一,无或轻度牙龈炎或牙周炎^[13]
Cohen综合征	VPS13B/COH1	参与蛋白糖基化,突变后中性粒细胞减少	复发性阿弗他口腔溃疡、牙龈炎、牙周炎^[14]
Chediak-Higashi综合征	LYST	损害溶酶体运输调节蛋白的正常功能,干扰溶酶体降解功能,中性粒细胞迁移、脱颗粒和吞噬受损	侵袭性牙周炎^[15]
白细胞黏附缺陷Ⅰ型	ITGB2	编码β2整合素亚基CD18,突变后中性粒细胞黏附缺陷,吞噬受损	早发的牙周炎^[16]
白细胞黏附缺陷Ⅱ型	SLC35C1	一种特定的岩藻糖转运蛋白,突变后中性粒细胞滚动受损	重度牙周炎、牙齿早失^[17]
惰性白细胞综合征	AIP1	肌动蛋白丝,阻止细胞极化或定向变形,突变后中性粒细胞减少、趋化受损	牙龈炎和牙周炎^[18]
掌跖角化-牙周破坏综合征	CTSC	组织蛋白酶C,丝氨酸蛋白酶活性必需,突变后中性粒细胞趋化及吞噬受损	早发的严重牙周炎、牙齿过早脱落^[19]
慢性肉芽肿病	gp91/CYBA/NCF1/ NCF2/NCF4等	参与NADPH氧化酶与呼吸爆发,突变后中性粒细胞数目正常,杀菌功能减弱,无法形成NETs	牙周炎、念珠菌病、反复细菌和真菌感染^[10]