A study on the variation of cytokine and electrolyte levels in rhesus macaques, cynomolgus monkeys, and Assamese macaques

Abstract

Background: Non-human primates (NPHs), such as rhesus macaques, cynomolgus monkeys, and Assamese macaques, play a crucial role in biomedical research. However, baseline cytokine and electrolyte data for these three species, particularly data stratified by age and sex, are limited. Therefore, the aim of this study was to establish and analyze age- and sex-specific cytokine and electrolyte profiles in these three species.

Methods: This study included 40 rhesus macaques (21 males, 19 females), 33 cynomolgus monkeys (17 males, 16 females), and 45 Assamese macaques (25 males, 20 females) classified by age (1–5 years, 6–12 years, >13 years) and sex. The levels of 23 immune function indicators and 5 electrolyte indicators were measured.

Results: Among the three monkey species, the levels of sCD40L, IL-18, MCP-1, MIP-1β, TGFa, K⁺, Na⁺, and Cl⁻ exhibited species-, sex-, and age-related differences. Comparison within the same species，sex had no significant impact on cytokine levels in NHPs but did affect electrolyte levels, particularly Cl⁻ and Na⁺ levels, in cynomolgus monkeys and Assamese macaques. Electrolyte levels in NHPs were not affected by age, whereas the levels of certain cytokines, particularly sCD40L, GM-CSF, and IL-10, varied with age. The remaining 21 cytokines demonstrated no significant age-related changes.

Conclusions: Significant variations in cytokine and electrolyte levels exist among different monkey species, sexes, and age groups. This research provides valuable resources for NHP researchers and sets the stage for further exploring the impacts of sex and age on NHP physiology and immune function.

Keywords

Assamese macaque / cynomolgus monkey / cytokines / electrolytes / rhesus macaque

References

[1] Jiang X, Fan Z, Li S, Yin H. A review on zoonotic pathogens associated with non-human primates: understanding the potential threats to humans. Microorganisms. 2023; 11(2): 246-260.

[2] Baxter MG, Roberts MT, Roberts JA, Rapp PR. Neuropsychology of cognitive aging in rhesus monkeys. Neurobiol Aging. 2023; 130():): 40-49.

[3] Jiang J, Li P, Yu J, et al. The complete mitochondrial genome of Assamese macaques (Macaca assamensis). Mitochondrial DNA A DNA Mapp Seq Anal. 2016; 27(1): 226-227.

[4] Shen H, Yang Z, Rodrigues AD. Cynomolgus monkey as an emerging animal model to study drug transporters: in vitro, in vivo, in vitro-to-in vivo translation. Drug Metab Dispos. 2022; 50(3): 299-319.

[5] Wu SH, Li X, Qin DD, et al. Induction of core symptoms of autism spectrum disorder by in vivo CRISPR/Cas9-based gene editing in the brain of adolescent rhesus monkeys. Sci Bull (Beijing). 2021; 66(9): 937-946.

[6] Yang J, Wang W, Chen Z, Lu S, et al. A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature. 2020; 586(7830): 572-577.

[7] Zhang J, Chen B, Lu J, et al. Brains of rhesus monkeys display Aβ deposits and glial pathology while lacking Aβ dimers and other Alzheimer's pathologies. Aging Cell. 2019b; 18(4): e12978.

[8] Anand RP, Layer JV, Heja D, et al. Design and testing of a humanized porcine donor for xenotransplantation. Nature. 2023; 622(7982): 393-401.

[9] Okajima D, Yasuda S, Maejima T, et al. Datopotamab Deruxtecan, a novel TROP2-directed antibody-drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021; 20(12): 2329-2340.

[10] Zhang B, Zhou Z, Zhou Y, et al. Social-valence-related increased attention in rett syndrome cynomolgus monkeys: an eye-tracking study. Autism Res. 2019a; 12(11): 1585-1597.

[11] Cooper MA, Bernstein IS. Counter aggression and reconciliation in Assamese macaques (Macaca assamensis). Am J Primatol. 2002; 56(4): 215-230.

[12] Mu D, Zhu JW, Liu FL, Zheng HY, Zheng YT. Association of TRIMCyp and TRIM5α from assam macaques leads to a functional trade-off between HIV-1 and N-MLV inhibition. Sci China Life Sci. 2018; 61(8): 954-965.

[13] Liu C, Chu D, Kalantar-Zadeh K, George J, Young HA, Liu G. Cytokines: from clinical significance to quantification. Adv Sci (Weinh). 2021; 8(15): e2004433.

[14] Dong C. Cytokine regulation and function in T cells. Annu Rev Immunol. 2021; 39: 51-76.

[15] Jarczak D, Nierhaus A. Cytokine storm-definition, causes, and implications. Int J Mol Sci. 2022; 23(19): 11740-11769.

[16] McDonough AA, Layton AT. Sex differences in renal electrolyte transport. Curr Opin Nephrol Hypertens. 2023; 32(5): 467-475.

[17] Painter A, Carius BM. Prehospital electrolyte care: a review of symptoms, evaluation, and management. J Spec Oper Med. 2022; 22(2): 80-86.

[18] Chamanza R, Amuzie CJ, Chilton J, Engelhardt JA. Special issue on the pathobiology of laboratory nonhuman primates: a review of species, substrain, geographical origin, age, and modality-related factors. Toxicol Pathol. 2022; 50(5): 548-551.

[19] Gaska JM, Parsons L, Balev M, et al. Conservation of cell-intrinsic immune responses in diverse nonhuman primate species. Life Sci Alliance. 2019; 2(5): e201900495.

[20] Saravanan C, Flandre T, Hodo CL, et al. Research relevant conditions and pathology in nonhuman primates. ILAR J. 2020; 61(2-3): 139-166.

[21] Singh VK, Carpenter AD, Janocha BL, et al. Radiosensitivity of rhesus nonhuman primates: consideration of sex, supportive care, body weight, and age at time of exposure. Expert Opin Drug Discov. 2023; 18(7): 797-814.

[22] Mäkitalo B, Andersson M, Areström I, et al. ELISpot and ELISA analysis of spontaneous, mitogen-induced and antigen-specific cytokine production in cynomolgus and rhesus macaques. J Immunol Methods. 2002; 270(1): 85-97.

[23] Kessler MJ, Rawlins RG, London WT. The hemogram, serum biochemistry, and electrolyte profile of aged rhesus monkeys (Macaca mulatta). J Med Primatol. 1983; 12(4): 184-191.

[24] Bonfanti U, Lamparelli D, Colombo P, Bernardi C. Hematology and serum chemistry parameters in juvenile cynomolgus monkeys (Macaca fascicularis) of Mauritius origin: comparison between purpose-bred and captured animals. J Med Primatol. 2009a; 38(4): 228-235.

[25] Koga T, Kanefuji K, Nakama K. Individual reference intervals of hematological and serum biochemical parameters in cynomolgus monkeys. Int J Toxicol. 2005; 24(5): 377-385.

[26] Perretta G, Violante A, Scarpulla M, Beciani M, Monaco V. Normal serum biochemical and hematological parameters in Macaca fascicularis. J Med Primatol. 1991; 20(7): 345-351.

[27] Sugimoto Y, Hanari K, Narita H, Honjo S. Normal hematologic values in the cynomolgus monkeys aged from 1 to 18 years. Jikken Dobutsu. 1986; 35(4): 443-447.

[28] Smucny DA, Allison DB, Ingram DK, et al. Changes in blood chemistry and hematology variables during aging in captive rhesus macaques (Macaca mulatta). J Med Primatol. 2001; 30(3): 161-173.

[29] Yoshida T, Suzuki K, Cho F, Honjo S. Age-related changes in hematological and serum biochemical values in cynomolgus monkeys (Macaca fascicularis) bred and reared using the indoor individually-caged system. Jikken Dobutsu. 1986; 35(3): 329-338.

[30] Ihrig M, Tassinary LG, Bernacky B, Keeling ME. Hematologic and serum biochemical reference intervals for the chimpanzee (pan troglodytes) categorized by age and sex. Comp Med. 2001; 51(1): 30-37.

[31] Harewood WJ, Gillin A, Hennessy A, Armistead J, Horvath JS, Tiller DJ. Biochemistry and haematology values for the baboon (Papio hamadryas): the effects of sex, growth, development and age. J Med Primatol. 1999; 28(1): 19-31.

[32] Chen Y, Ono F, Yoshida T, Yoshikawa Y. Relationship between body weight and hematological and serum biochemical parameters in female cynomolgus monkeys (Macaca fascicularis). Exp Anim. 2002; 51(2): 125-131.

[33] Liddie S, Goody RJ, Valles R, Lawrence MS. Clinical chemistry and hematology values in a Caribbean population of African green monkeys. J Med Primatol. 2010; 39(6): 389-398.

[34] Chen Y, Qin S, Ding Y, et al. Reference values of clinical chemistry and hematology parameters in rhesus monkeys (Macaca mulatta). Xenotransplantation. 2009; 16(6): 496-501.

[35] Kim CY, Lee HS, Han SC, et al. Hematological and serum biochemical values in cynomolgus monkeys anesthetized with ketamine hydrochloride. J Med Primatol. 2010; 34(2): 96-100.

[36] Lugo-Roman LA, Rico PJ, Sturdivant R, Burks R, Settle TL. Effects of serial anesthesia using ketamine or ketamine/medetomidine on hematology and serum biochemistry values in rhesus macaques (Macaca Mulatta). J Med Primatol. 2010; 39(1): 41-49.

[37] Venkatesan R, Nagarajan P, Rajaretnam RS, Majumdar SS. Hematologic and serum biochemical values in aged female bonnet macaques (Macaca radiata) anesthetized with ketamine hydrochloride. J Am Assoc Lab Anim Sci. 2006; 45(2): 45-48.

[38] Fujiwara T, Suzaki Y, Yoshioka Y, Honjo S. Hematological changes during pregnancy and postpartum period in cynomolgus monkeys (Macaca fascicularis). Exp Anim. 1974; 23: 137-146.

[39] Suzuki T, Suzuki N, Shimoda K, Nagasawa H. Hematological and serum biochemical values in pregnant and postpartum females of the squirrel monkey (Saimiri sciureus). Exp Anim. 1996; 45(1): 39-43.

[40] Mackenzie M, Lowenstine L, Lalchandani R, Lerche N, Gardner M. Hematologic abnormalities in simian acquired immune deficiency syndrome. Lab Anim Sci. 1986; 36(1): 14-19.

[41] Sammons LS, Kenyon RH, Burger GT, Pedersen CE, Spertzel RO. Changes in blood serum constituents and hematologic values in Macaca mulatta with Rocky Mountain spotted fever. Am J Vet Res. 1976; 37(6): 725-730.

[42] Yang XL, Liu YB. Advances in pathobiology of primary central nervous system lymphoma. Chin Med J. 2017; 130(16): 1973-1979.

[43] Debisarun PA, Kilic G, de Bree LCJ, et al. The impact of BCG dose and revaccination on trained immunity. Clin Immunol. 2023; 246: 109208.

[44] Roe K. An inflammation classification system using cytokine parameters. Scand J Immunol. 2021; 93(2): e12970.

[45] Jiang P, Zhang Y, Ru B, et al. Systematic investigation of cytokine signaling activity at the tissue and single-cell levels. Nat Methods. 2021; 18(10): 1181-1191.

[46] Karki R, Kanneganti TD. The ‘cytokine storm’: molecular mechanisms and therapeutic prospects. Trends Immunol. 2021; 42(8): 681-705.

[47] Mohseni Afshar Z, Barary M, Babazadeh A, et al. The role of cytokines and their antagonists in the treatment of COVID-19 patients. Rev Med Virol. 2023; 33(1): e2372.

[48] Tadokoro Y, Hirao A. The role of nutrients in maintaining hematopoietic stem cells and healthy hematopoiesis for life. Int J Mol Sci. 2022; 23(3): 1574-1589.

[49] Terry J. The major electrolytes: sodium, potassium, and chloride. J Intraven Nurs. 1994; 17(5): 240-247.

[50] Kumari J, Rathore MS. Na (+)/K (+)-ATPase a primary membrane transporter: an overview and recent advances with special reference to algae. J Membr Biol. 2020; 253(3): 191-204.

[51] Jacoby N. Electrolyte disorders and the nervous system. Continuum (Minneap Minn). 2020; 26(3): 632-658.

[52] Elorza-Vidal X, Gaitán-Peñas H, Estévez R. Chloride channels in astrocytes: structure, roles in brain homeostasis and implications in disease. Int J Mol Sci. 2019; 20(5): 1034-1056.

[53] Park E, Campbell EB, MacKinnon R. Structure of a CLC chloride ion channel by cryo-electron microscopy. Nature. 2017; 541(7638): 500-505.

[54] Thiemann A, Gründer S, Pusch M, Jentsch TJ. A chloride channel widely expressed in epithelial and non-epithelial cells. Nature. 1992; 356(6364): 57-60.

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