Phenotypic features and subset composition of monocytes in acute pancreatitis

The aim of our research was to study the features of activation receptor expression on various subsets of blood monocytes in patients with acute pancreatitis (AP). 69 patients aged 37-62 years with moderateand severe-grade AP were examined. The diagnosis of AP was based on the results of clinical, laboratory and instrumental examination. Phenotype and subpopulation composition of monocytes were studied by flow cytometry. Alterations in blood monocytes phenotypes and increased expression of activation receptors were noted in patients during the initial period of AP. Thus, an increased proportion of monocytes in the blood of patients with AP with co-expression of CD45RO and CD62L was detected, along with increased number of cells expressing CD25 receptor. An increased level of migratory monocyte activity in AP could be linked with CXCR4 and CCR5 receptors. Altered subset composition during the acute period of AP was linked with 2-fold increased levels of “non-classical” monocytes. The proportion of cells with expression of chemokine receptors in the subset composition of monocytes changed in AP. Thus, the number of “classical” and “nonclassical” monocytes with CXCR4 was increased within total monocyte subset in the patients. Meanwhile, the content of cell subsets with CCR5 receptor expression was almost uniformly increased. The changed expression levels of activation receptors also characterized the activation features of various monocyte subsets in patients during the initial period of AP. Elevated CCR5 was detected in AP only on “classical” monocytes, whereas increased CD64 was found only on “non-classical” monocytes. Elevated HLA-DR expression was detected on “classical” and “intermediate” monocytes of patients with AP but a high level of CXCR4 expression was found on all monocytes subsets. The registered changes in phenotype and subset composition of monocytes in patients during the initial period of the disease seem to characterize the mode of monocyte involvement into the inflammatory process in AP thus revealing not only pro-inflammatory reaction of monocytes, along with increased activity of monocyte subset with anti-inflammatory function.

1. Kozlov V.A., Tikhonova E.P., Savchenko A.A., Kudryavtsev I.V., Andronova N.V., Anisimova E.N., Golovkin A.S., Demina D.V., Zdzitovetsky D.E.E., Kalinina Y.S., Kasparov E.V., Kozlov I.G., Korsunsky I.A., Kudlay D.A., Kuzmina T.Yu., Minoranskaya N.S., Prodeus A.P., Starikova E.A., Cherdantsev D.V., Chesnokov A.B., Shesternya P.A., Borisov A.G. Clinical immunology. A practical guide for infectious disease specialists. Krasnoyarsk: Polikor, 2021. 563 p.

2. Musailov V.A., Eryashev A.F., Kharitonov V.V., Parkhomenko S.A., Chernekhovskaya N.E. Endolymphatic drug therapy for acute pancreatitis. Gospitalnaya meditsina: nauka i praktika = Hospital Medicine: Science and Practice, 2023, Vol. 6, no. 1, pp. 33-38. (In Russ.)

3. Otdelnov L.A., Mukhin A.S. Abdominal compartment syndrome in severe acute pancreatitis (review of literature). Vestnik khirurgii imeni I.I. Grekova = Grekov’s Bulletin of Surgery, 2020, Vol. 179, no. 2, pp. 73-78. (In Russ.)

4. Acute pancreatitis. Clinical recommendations. Мoscow, 2023. 55 p.

5. Savchenko A.A., Borisov A.G., Zdzitovetskiy D.E., Kudryavtsev I.V., Medvedev A.Yu., Moshev A.V., Gvozdev I.I. Phenotypic profile and functional activity of monocytes in the patients with acute pancreatitis. Meditsinskaya immunologiya = Medical Immunology (Russia), 2017, Vol. 19, no. 1, pp. 45-54. (In Russ.)doi: 10.15789/1563-0625-2017-1-45-54.

6. Savchenko A.A., Borisov A.G., Zdzitovetskiy D.E., Medvedev A.Yu., Gvozdev I.I. Dependence of neutrophil respiratory burst on their metabolic state in the patients with acute destructive pancreatitis of different severity. Meditsinskaya immunologiya = Medical Immunology (Russia), 2019, Vol. 21, no. 1, pp. 77-88. (In Russ.) doi: 10.15789/1563-0625-2019-1-77-88.

7. Teterin Yu.S., Kulikov Yu.D., Rogal M.L., Yartsev P.A., Askerov A.Ch., Eletskaya E.S., Novikov S.V. Endoscopic transluminal drainage for infected pancreatic necrosis. Khirurgiya. Zhurnal im. N.I. Pirogova = Pirogov Russian Journal of Surgery , 2022, no. 2, pp. 17-23 (In Russ.)

8. Ahmed M.G.T., Limmer A., Hartmann M. CD45RA and CD45RO Are Regulated in a Cell-Type Specific Manner in Inflammation and Sepsis. Cells, 2023, Vol. 12, no. 14, 1873. doi: 10.3390/cells12141873.

9. Ahmed M.G.T., Limmer A., Sucker C., Fares K.M., Mohamed S.A., Othman A.H., Berger M.M., Brenner T., Hartmann M. Differential Regulation of CD45 Expression on Granulocytes, Lymphocytes, and Monocytes in COVID-19. J. Clin. Med., 2022, Vol. 11, no. 14, 4219. doi: 10.3390/jcm11144219.

10. Bianchi M.E., Mezzapelle R. The Chemokine receptor CXCR4 in cell proliferation and tissue regeneration. Front. Immunol., 2020, Vol. 11, 2109. doi: 10.3389/fimmu.2020. 02109.

11. Brezovec N., Perdan-Pirkmajer K., Kuret T., Burja B., Sodin-Šemrl S., Čučnik S., Lakota K. Increased L-Selectin on monocytes is linked to the autoantibody profile in systemic sclerosis. Int. J. Mol. Sci., 2022, Vol. 23, no. 4, 2233. doi: 10.3390/ijms23042233.

12. Britton C., Poznansky M.C., Reeves P. Polyfunctionality of the CXCR4/CXCL12 axis in health and disease: Implications for therapeutic interventions in cancer and immune-mediated diseases. FASEB J., 2021, Vol. 35, no. 4, e21260. doi: 10.1096/fj.202001273R.

13. Brown L.E., Zhang D., Cui W. Flow cytometric analysis of monocytes and granulocytes may be useful in the distinction of myeloid neoplasms from reactive conditions: a single institution experience and literature review. Ann. Clin. Lab. Sci., 2020, Vol. 50, no. 3, pp. 327-332.

14. Caspar B., Cocchiara P., Melet A., van Emelen K., van der Aa A., Milligan G., Herbeuval J.P. CXCR4 as a novel target in immunology: moving away from typical antagonists. Future Drug Discov., 2022, Vol. 4, no. 2, FDD77. doi: 10.4155/fdd-2022-0007.

15. Da Silva E., Scott M.G.H., Enslen H., Marullo S. Control of CCR5 Cell-Surface Targeting by the PRAF2 Gatekeeper. Int. J. Mol. Sci., 2023, Vol. 24, no. 24, 17438. doi: 10.3390/ijms242417438.

16. de Freitas C.G., Farias M.G. Evaluation of HLA-DR expression in monocytes and CD64 in neutrophils as A predictor of SEPSIS/sirs in the infectious-inflammatory process. J. Immunol. Methods, 2024, Vol. 524, 113589. doi: 10.1016/j.jim.2023.113589.

17. Di Marino D., Conflitti P., Motta S., Limongelli V. Structural basis of dimerization of chemokine receptors CCR5 and CXCR4. Nat. Commun., 2023, Vol. 14, no. 1, 6439. doi: 10.1038/s41467-023-42082-z.

18. Fanelli M., Petrone V., Maracchioni C., Chirico R., Cipriani C., Coppola L., Malagnino V., Teti E., Sorace C., Zordan M., Vitale P., Iannetta M., Balestrieri E., Rasi G., Grelli S., Malergue F., Sarmati L., Minutolo A., Matteucci C. Persistence of circulating CD169+monocytes and HLA-DR downregulation underline the immune response impairment in PASC individuals: the potential contribution of different COVID-19 pandemic waves. Curr. Res. Microb. Sci., 2023, Vol. 6, 100215. doi: 10.1016/j.crmicr.2023.100215.

19. Ferrero M.R., Tavares L.P., Garcia C.C. The dual role of CCR5 in the course of influenza infection: exploring treatment opportunities. Front. Immunol., 2022, Vol. 12, 826621. doi: 10.3389/fimmu.2021.826621.

20. González-Arriagada W.A., García I.E., Martínez-Flores R., Morales-Pison S., Coletta R.D. Therapeutic Perspectives of HIV-Associated Chemokine Receptor (CCR5 and CXCR4) Antagonists in Carcinomas. Int. J. Mol. Sci., 2022, Vol. 24, no. 1, 478. doi: 10.3390/ijms24010478.

21. Goshima T., Ieguchi K., Onishi N., Shimizu T., Takayanagi D., Watanabe M., Fujimoto Y., Ohkuma R., Suzuki R., Tsurui T., Mura E., Iriguchi N., Ishiguro T., Shimokawa M., Hirasawa Y., Kubota Y., Ariizumi H., Horiike A., Yoshimura K., Tsuji M., Kiuchi Y., Kobayashi S., Fujishiro J., Hoffman R.M., Tsunoda T., Wada S. Nonclassical monocytes enhance the efficacy of immune checkpoint inhibitors on colon cancer in a syngeneic mouse model. Anticancer Res., 2024, Vol. 44, no. 1, pp. 23-29.

22. Gui M., Zhao B., Huang J., Chen E., Qu H., Mao E. Pathogenesis and therapy of coagulation disorders in severe acute pancreatitis. J. Inflamm. Res., 2023, Vol. 16, pp. 57-67.

23. Guilliams M., Mildner A., Yona S. Developmental and functional heterogeneity of monocytes. Immunity, 2018, Vol. 49, no. 4, pp. 595-613.

24. Hichami A., Saidi H., Khan A.S., Degbeni P., Khan N.A. In vitro functional characterization of type-i taste bud cells as monocytes/macrophages-like which secrete proinflammatory cytokines. Int. J. Mol. Sci., 2023, Vol. 24, no. 12, 10325. doi: 10.3390/ijms241210325.

25. Iloba I., McGarry S.V., Yu L., Cruickshank D., Jensen G.S. Differential immune-modulating activities of cell walls and secreted metabolites from probiotic bacillus coagulans JBI-YZ6.3 under normal versus inflamed culture conditions. Microorganisms, 2023, Vol. 11, no. 10, 2564. doi: 10.3390/microorganisms11102564.

26. Kim S.K., Choe J.Y., Park K.Y. CXCL12 and CXCR4 as novel biomarkers in uric acid-induced inflammation and patients with gouty arthritis. Biomedicines, 2023, Vol. 11, no. 3, 649. doi: 10.3390/biomedicines11030649.

27. Liu S., Luo W., Szatmary P., Zhang X., Lin J.W., Chen L., Liu D., Sutton R., Xia Q., Jin T., Liu T., Huang W. Monocytic HLA-DR expression in immune responses of acute pancreatitis and COVID-19. Int. J. Mol. Sci., 2023, Vol. 24, no. 4, 3246. doi: 10.3390/ijms24043246.

28. Liu S., Szatmary P., Lin J.W., Wang Q., Sutton R., Chen L., Liu T., Huang W., Xia Q. Circulating monocytes in acute pancreatitis. Front. Immunol., 2022, Vol. 13, 1062849. doi: 10.3389/fimmu.2022. 1062849.

29. Luo H., Zhu Y., Guo B., Ruan Z., Liu Z., Fan Z., Zhao S. Causal relationships between CD25 on immune cells and hip osteoarthritis. Front. Immunol., 2023, Vol. 14, 1247710. doi: 10.3389/fimmu.2023. 1247710.

30. Padgett L.E., Araujo D.J., Hedrick C.C., Olingy C.E. Functional crosstalk between T cells and monocytes in cancer and atherosclerosis. J. Leukoc. Biol., 2020, Vol. 108, no. 1, pp. 297-308.

31. Pan L.L., Deng Y.Y., Wang R., Wu C., Li J., Niu W., Yang Q., Bhatia M., Gudmundsson G.H., Agerberth B., Diana J., Sun J. Lactose induces phenotypic and functional changes of neutrophils and macrophages to alleviate acute pancreatitis in mice. Front. Immunol., 2018, Vol. 9, 751. doi: 10.3389/fimmu.2018.00751.

32. Peng C., Li Z., Yu X. The role of pancreatic infiltrating innate immune cells in acute pancreatitis. Int. J. Med. Sci., 2021, Vol. 18, no. 2, pp. 534-545.

33. Qu P.F., Li R., Xu C., Chai W., Li H., Fu J., Chen J.Y. A clinical pilot study to evaluate CD64 expression on blood monocytes as an indicator of periprosthetic joint infection. J. Bone Joint Surg. Am., 2020, Vol. 102, no. 17, e99. doi: 10.2106/JBJS.20.00057.

34. Rawat K., Tewari A., Li X., Mara A.B., King W.T., Gibbings S.L., Nnam C.F., Kolling F.W., Lambrecht B.N., Jakubzick C.V. CCL5-producing migratory dendritic cells guide CCR5+ monocytes into the draining lymph nodes. J. Exp. Med., 2023, Vol. 220, no. 6, e20222129. doi: 10.1084/jem.20222129.

35. Rutkowska E., Kwiecień I., Kłos K., Rzepecki P., Chciałowski A. Intermediate monocytes with PD-L1 and CD62L expression as a possible player in active SARS-CoV-2 infection. Viruses, 2022, Vol. 14, no. 4, 819. doi: 10.3390/v14040819.

36. Sadri F., Rezaei Z., Fereidouni M. The significance of the SDF-1/CXCR4 signaling pathway in the normal development. Mol. Biol. Rep., 2022, Vol. 49, no. 4, pp. 3307-3320. doi: 10.1007/s11033-021-07069-3.

37. Santos J., Wang P., Shemesh A., Liu F., Tsao T., Aguilar O.A., Cleary S.J., Singer J.P., Gao Y., Hays S.R., Golden J.A., Leard L., Kleinhenz M.E., Kolaitis N.A., Shah R., Venado A., Kukreja J., Weigt S.S., Belperio J.A., Lanier L.L., Looney M.R., Greenland J.R., Calabrese D.R. CCR5 drives NK cell-associated airway damage in pulmonary ischemia-reperfusion injury. JCI Insight, 2023, Vol. 8, no. 21, e173716. doi: 10.1172/jci.insight.173716.

38. Son A., Ahuja M., Schwartz D.M., Varga A., Swaim W., Kang N., Maleth J., Shin D.M., Muallem S. Ca2+ Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis. Gastroenterology, 2019, Vol. 157, no. 6, pp. 1660-1672.e2.

39. Trumet L., Ries J., Ivenz N., Sobl P., Wehrhan F., Lutz R., Kesting M., Weber M. Does surgery affect systemic immune response? А perioperative analysis of TGF-β, IL-8 and CD45RO. Front. Oncol., 2023, Vol. 13, 1307956. doi: 10.3389/fonc.2023.1307956.

40. Walkowska J., Zielinska N., Karauda P., Tubbs R.S., Kurtys K., Olewnik Ł. The pancreas and known factors of acute pancreatitis. J. Clin. Med., 2022, Vol. 11, no. 19, 5565. doi: 10.3390/jcm11195565.

41. Wan J., Yang X., Ren Y., Li X., Zhu Y., Haddock A.N., Ji B., Xia L., Lu N. Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model. Cell Death Dis., 2019, Vol. 10, no. 4, 303. doi: 10.1038/s41419-019-1545-x.

42. Werner Y., Mass E., Ashok Kumar P., Ulas T., Händler K., Horne A., Klee K., Lupp A., Schütz D., Saaber F., Redecker C., Schultze J.L., Geissmann F., Stumm R. CXCR4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke. Nat. Neurosci., 2020, Vol. 23, no. 3, pp. 351-362.

43. Xue J., Sharma V., Habtezion A. Immune cells and immune-based therapy in pancreatitis. Immunol. Res., 2014, Vol. 58, no. 2-3, pp. 378-386. 44. Yu J., Zhou X., Shen L. CXCR4-targeted radiopharmaceuticals for the imaging and therapy of malignant tumors. Molecules, 2023, Vol. 28, no. 12, 4707. doi: 10.3390/molecules28124707.

44. Zhang B., Xiao Q., Ma Q., Han L. Clinical treatment for persistent inflammation, immunosuppression and catabolism syndrome in patients with severe acute pancreatitis (Review). Exp. Ther. Med., 2023, Vol. 26, no. 4, 495. doi: 10.3892/etm.2023.12194.

45. Zhou R., Bu W., Fan Y., Du Z., Zhang J., Zhang S., Sun J., Li Z., Li J. Dynamic changes in serum cytokine profile in rats with severe acute pancreatitis. Medicina (Kaunas), 2023, Vol. 59, no. 2, 321. doi: 10.3390/medicina59020321.