Журнал микробиологии, эпидемиологии и иммунобиологии. 2021; 98: 176-183
Ассоциация увеличения количества циркулирующих CD62LloCXCR4hi-нейтрофилов с распространённостью каротидного атеросклероза
Долгушин И. И., Генкель В. В., Батурина И. Л., Емельянов И. В., Савочкина А. Ю., Шапошник И. И.
https://doi.org/10.36233/0372-9311-67Аннотация
Введение. Изучение роли нейтрофилов в инициации и прогрессировании атеросклероза и развитии его осложнений активно ведется лишь на протяжении последних нескольких лет. К настоящему времени имеются данные, свидетельствующие о важной роли оси CXCL12/CXCR4 в поддержании воспаления при различных хронических воспалительных заболеваниях путем задержки нейтрофилов в очагах воспаления.
Цель исследования — установить диагностическую и прогностическую значимость циркулирующих CD62LloCXCR4hi-нейтрофилов у пациентов с каротидным атеросклерозом.
Материалы и методы. Обследовали 75 пациентов (52% мужчин и 48% женщин) в возрасте 40–64 лет без установленных атеросклеротических сердечно-сосудистых заболеваний. Всем пациентам проводили дуплексное сканирование артерий каротидного бассейна. Фенотипирование и дифференцировку субпопуляций нейтрофилов осуществляли методом проточной цитометрии с использованием конъюгатов моноклональных антител CD16, CD11b, CD62L, CD182 (CXCR2) и CD184 (CXCR4).
Результаты. Атеросклеротические бляшки в артериях каротидного бассейна были выявлены у 72% пациентов, при этом у большинства пациентов диагностировано стенозирование более одной сонной артерии (СА). Увеличение количества циркулирующих CXCR4hi-нейтрофилов ассоциировалось с уровнями общего холестерина (r = 0,377; p = 0,001), холестерина липопротеинов низкой плотности (r = 0,293; p = 0,014) и триглицеридов (r = 0,388; p = 0,003). Выявлены прямые корреляционные связи между количеством циркулирующих CXCR4hi-нейтрофилов и суммарным процентом стенозирования СА (r = 0,300; p = 0,011), а кроме того — с количеством стенозированных СА (r = 0,291; p = 0,034). Отмечено статистически значимое нарастание количества CXCR4hi-нейтрофилов по мере увеличения количества стенозированных СА (p = 0,025). По данным ROC-анализа, увеличение количества CXCR4hi-нейтрофилов ≥260 кл/мкл позволяло диагностировать стенозирующее поражение 4 СА с чувствительностью 71,4% и специфичностью 76,6%.
Заключение. У пациентов с каротидным атеросклерозом увеличение циркулирующих CD62LloCXCR4hi-нейтрофилов ассоциировалось с увеличением числа стенозированных СА при отсутствии значимых изменений в других оцениваемых субпопуляциях нейтрофильных гранулоцитов. Увеличение количества CD62LloCXCR4hi-нейтрофилов позволяло с достаточной чувствительностью и специфичностью диагностировать стенозирующее поражение 4 СА.
Список литературы
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17. Sjaarda J., Gerstein H., Chong M., Yusuf S., Meyre D., Anand S.S., et al. Blood CSF1 and CXCL12 as causal mediators of coronary artery disease. J. Am. Coll. Cardiol. 2018; 72(3): 300–10. https://doi.org/10.1016/j.jacc.2018.04.067
18. Tavakolian Ferdousie V., Mohammadi M., Hassanshahi G., Khorramdelazad H., Khanamani Falahati-Pour S., Mirzaei M., et al. Serum CXCL10 and CXCL12 chemokine levels are associated with the severity of coronary artery disease and coronary artery occlusion. Int. J. Cardiol. 2017; 233: 23–8. https://doi.org/10.1016/j.ijcard.2017.02.011
19. De Filippo K., Rankin S.M. CXCR4, the master regulator of neutrophil trafficking in homeostasis and disease. Eur. J. Clin. Invest. 2018; 48(Suppl. 2): e12949. https://doi.org/10.1111/eci.12949
20. Uhl B., Vadlau Y., Zuchtriegel G., Nekolla K., Sharaf K., Gaertner F., et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. 2016; 128: 2327–37. https://doi.org/10.1182/blood-2016-05-718999
21. Gutierrez J.A., Aday A.W., Patel M.R., Jones W.S. Polyvascular disease: reappraisal of the current clinical landscape. Circ. Cardiovasc. Interv. 2019; 12(12): e007385. https://doi.org/10.1161/CIRCINTERVENTIONS.119.007385
Journal of microbiology, epidemiology and immunobiology. 2021; 98: 176-183
Association of the increased circulating CD62LloCXCR4hi neutrophil count with carotid atherosclerosis
Dolgushin I. I., Genkel V. V., Baturina I. L., Emelyanov I. V., Savochkina A. Y., Shaposhnik I. I.
https://doi.org/10.36233/0372-9311-67Abstract
Introduction. The role of neutrophils in the initiation and progression of atherosclerosis as well as in the development of its complications has received scientific attention only in the recent years. Today, there is growing evidence to support a role of the CXCL12/CXCR4 axis in sustained inflammation during different chronic inflammatory diseases by retaining neutrophils at inflammatory sites.
The aim of the study is to assess the diagnostic and prognostic significance of circulating CD62LloCXCR4 hi neutrophils in patients with carotid atherosclerosis.
Materials and methods. A total of 75 patients (52% of men and 48% of women) aged 40 to 64 years were examined. None of them were diagnosed with atherosclerotic cardiovascular diseases. All the patients underwent carotid artery duplex scanning. The flow cytometry and CD16, CD11b, CD62L, CD182 (CXCR2) and CD184 (CXCR4) conjugated monoclonal antibodies were used for phenotyping and differentiation of neutrophil subpopulations.
Results. Atherosclerotic plaques in carotid arteries were detected in 72% of the patients; most of the patients were diagnosed with stenosis development in more than one of the carotid arteries (CA). The elevated levels of circulating CXCR4h neutrophils were associated with the levels of total cholesterol (r = 0.377; p = 0.001), low-density lipoprotein (LDL) cholesterol (r = 0.293; p = 0.014) and triglycerides (r = 0.388; p = 0.003). The study revealed direct correlation between the circulating CXCR4 hi neutrophil count and the cumulative percentage of CA stenosis (r = 0.300; p = 0.011), including the number of stenosed CA (r = 0.291; p = 0.034). It was also found that CXCR4 hi neutrophil counts demonstrated a statistically significant increase along with the increased number of stenosed CA (p = 0.025). The ROC analysis findings show that the elevated CXCR4 hi neutrophil counts ≥260 cells/μL made it possible to diagnose stenotic lesion of 4 CAs with a sensitivity of 71.4% and specificity reaching 76.6%.
Conclusion. In patients with carotid atherosclerosis, the increased count of circulating CD62LloCXCR4 hi neutrophils was associated with the increased number of stenosed CAs, while no significant changes were observed in the other examined subpopulations of neutrophil granulocytes. The increased CD62LloCXCR4 hi neutrophil count made it possible to diagnose stenotic lesion of 4 CAs with a sufficient sensitivity and specificity.
References
1. Silvestre-Roig C., Braster Q., Ortega-Gomez A., Soehnlein O. Neutrophils as regulators of cardiovascular inflammation. Nat. Rev. Cardiol. 2020; 17(6): 327–40. https://doi.org/10.1038/s41569-019-0326-7
2. Dolgushin I.I. Neitrofil'nye granulotsity: novye litsa starykh znakomykh. Byulleten' sibirskoi meditsiny. 2019; 18(1): 30–7. https://doi.org/10.20538/1682-0363-2019-1-30-37
3. Xue Y., Wu Y., Wang Q., Xue L., Su Z., Zhang C. Cellular vehicles based on neutrophils enable targeting of atherosclerosis. Mol. Pharm. 2019; 16(7): 3109–20. https://doi.org/10.1021/acs.molpharmaceut.9b00342
4. Geng S., Zhang Y., Lee C., Li L. Novel reprogramming of neutrophils modulates inflammation resolution during atherosclerosis. Sci. Adv. 2019; 5(2): eaav2309. https://doi.org/10.1126/sciadv.aav2309
5. Adrover J.M., Nicolás-Ávila J.A., Hidalgo A. Aging: a temporal dimension for neutrophils. Trends Immunol. 2016; 37(5): 334– 45. https://doi.org/10.1016/j.it.2016.03.005
6. Rosales C. Neutrophil: a cell with many roles in inflammation or several cell types? Front. Physiol. 2018; 9: 113. https://doi.org/10.3389/fphys.2018.00113
7. Bonaventura A., Montecucco F., Dallegri F., Carbone F., Lüscher T.F., Camici G.G., et al. Novel findings in neutrophil biology and their impact on cardiovascular disease. Cardiovasc. Res. 2019; 115(8): 1266–85. https://doi.org/10.1093/cvr/cvz084
8. Isles H.M., Herman K.D., Robertson A.L., Loynes C.A., Prince L.R., Elks P.M., et al. The CXCL12/CXCR4 signaling axis retains neutrophils at inflammatory sites in zebrafish. Front. Immunol. 2019; 10: 1784. https://doi.org/10.3389/fimmu.2019.01784
9. Hartl D., Krauss-Etschmann S., Koller B., Hordijk P.L., Kuijpers T.W., Hoffmann F., et al. Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases. J. Immunol. 2008; 181(11): 8053–67. https://doi.org/10.4049/jimmunol.181.11.8053
10. García-Cuesta E.M., Santiago C.A., Vallejo-Díaz J., Juarranz Y., Rodríguez-Frade J.M., Mellado M. The role of the CXCL12/ CXCR4/ACKR3 axis in autoimmune diseases. Front. Endocrinol. (Lausanne). 2019; 10: 585. https://doi.org/10.3389/fendo.2019.00585
11. Li L., Du Z., Rong B., Zhao D., Wang A., Xu Y., et al. Foam cells promote atherosclerosis progression by releasing CXCL12. Biosci. Rep. 2020; 40(1): BSR20193267. https://doi.org/10.1042/BSR20193267
12. Merckelbach S., van der Vorst E.P.C., Kallmayer M., Rischpler C., Burgkart R., Döring Y., et al. Expression and cellular localization of CXCR4 and CXCL12 in human carotid atherosclerotic plaques. Thromb. Haemost. 2018; 118(1): 195–206. https://doi.org/10.1160/TH17-04-0271
13. Sprynger M., Rigo F., Moonen M., Aboyans V., Edvardsen T., de Alcantara M.L., et al. Focus on echovascular imaging assessment of arterial disease: complement to the ESC guidelines (PARTIM 1) in collaboration with the Working Group on Aorta and Peripheral Vascular Diseases. Eur. Heart J. Cardiovasc. Imaging. 2018; 19(11): 1195–221. https://doi.org/10.1093/ehjci/jey103
14. Mozzini C., Roscia G., Casadei A., Cominacini L. Searching the perfect ultrasonic classification in assessing carotid artery stenosis: comparison and remarks upon the existing ultrasound criteria. J. Ultrasound. 2016; 19(2): 83–90. https://doi.org/10.1007/s40477-016-0193-6
15. Mach F., Baigent C., Catapano A.L., Koskinas K.C., Casula M., Badimon L., et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J. 2020; 41(1): 111–88. https://doi.org/10.1093/eurheartj/ehz455
16. Saranchina Yu.V., Dutova S.V., Kilina O.Yu., Khanarin N.V., Kulakova T.S. Rol' neitrofilov v patogeneze ateroskleroza. Kardiovaskulyarnaya terapiya i profilaktika. 2018; 17(6): 110–6. https://doi.org/10.15829/1728-8800-2018-6-110-116
17. Sjaarda J., Gerstein H., Chong M., Yusuf S., Meyre D., Anand S.S., et al. Blood CSF1 and CXCL12 as causal mediators of coronary artery disease. J. Am. Coll. Cardiol. 2018; 72(3): 300–10. https://doi.org/10.1016/j.jacc.2018.04.067
18. Tavakolian Ferdousie V., Mohammadi M., Hassanshahi G., Khorramdelazad H., Khanamani Falahati-Pour S., Mirzaei M., et al. Serum CXCL10 and CXCL12 chemokine levels are associated with the severity of coronary artery disease and coronary artery occlusion. Int. J. Cardiol. 2017; 233: 23–8. https://doi.org/10.1016/j.ijcard.2017.02.011
19. De Filippo K., Rankin S.M. CXCR4, the master regulator of neutrophil trafficking in homeostasis and disease. Eur. J. Clin. Invest. 2018; 48(Suppl. 2): e12949. https://doi.org/10.1111/eci.12949
20. Uhl B., Vadlau Y., Zuchtriegel G., Nekolla K., Sharaf K., Gaertner F., et al. Aged neutrophils contribute to the first line of defense in the acute inflammatory response. Blood. 2016; 128: 2327–37. https://doi.org/10.1182/blood-2016-05-718999
21. Gutierrez J.A., Aday A.W., Patel M.R., Jones W.S. Polyvascular disease: reappraisal of the current clinical landscape. Circ. Cardiovasc. Interv. 2019; 12(12): e007385. https://doi.org/10.1161/CIRCINTERVENTIONS.119.007385
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