Biomarkers of Immunity: Monocytes

Optimal Takeaways

Monocytes are white blood cells that play an active role in immune defense but can also become pathogenic, potentially damaging tissues and even supporting tumor growth. Monocytes differentiate into macrophages but can also be converted into osteoclasts and microglial cells.

Elevations in monocytes are associated with low-grade inflammation seen with CVD, metabolic syndrome, diabetes, and other inflammatory disorders. Monocytes are also associated with infections and autoimmune disorders. Vitamin C may help reduce the negative effects of monocytes/macrophages.

Low levels of monocytes may be seen with certain malignancies, immune disorders, and corticosteroid use.

Monocytes, Absolute    

Standard Range: 0.20 – 0.95 k/cumm (0.20 – 0.95 giga/L)

The ODX Range:  0.20 – 0.40 k/cumm (0.20 – 0.40 giga/L)

Monocytes %      

Standard Range: 4.00 – 13.00 %

The ODX Range: 4.00 - 7.00%          

Low monocyte counts are associated with monocytopenia, aplastic anemia, hairy-cell leukemia (Pagana 2021), inherited immune disorders, some infections, corticosteroid use, and chemotherapy (Deyrup 2022).

High monocyte counts are associated with monocytosis, chronic inflammatory disorders, viral infections including infectious mononucleosis, tuberculosis, chronic ulcerative colitis, and parasitic disease including malaria (Pagana 2021), chronic infections, chronic inflammation, autoimmune disorders, myeloid neoplasms (Deyrup 2022), more severe hepatocellular carcinoma with worse overall survival (Yu 2021), cardiometabolic dysfunction, metabolic syndrome, and CVD mortality (Kim 2008).

Overview

Monocytes are phagocytic, cytokine-producing white blood cells with some similarities to neutrophils, though monocytes are produced more rapidly and can remain in circulation longer than neutrophils (Pagana 2021). Monocytes play both a protective and a pathogenic role throughout the body. They differentiate into macrophages and are major contributors to immune system regulation. Depending on the subset, monocytes support cytotoxic T-cell activity and anti-tumor activity and travel to tissues as needed to supply ample precursors to macrophages lost to injury or infection. However, some activities may damage tissue or, in some cases, support tumor growth by inducing resistance to chemotherapy (Murray 2018).

Monocytes differentiate into macrophages and serve as precursors to other cells in the mononuclear phagocytic system, including osteoclasts and microglial cells in connective tissue and organs (Tigner 2021). The differentiation of monocytes into bone-resorbing osteoclasts is ultimately controlled by vitamin D (Carlberg 2019).

Monocytes are early responders during acute infection but may contribute to chronic disease over time. They also play a custodial, anti-inflammatory role in the maintenance of vascular homeostasis, highlighting their multifaceted roles in the body (Narasimhan 2019).

Elevated monocytes can be seen with cardiometabolic dysfunction, metabolic syndrome, and increased risk of CVD mortality, conditions associated with low-grade inflammation. The lowest risk for obesity, hypertension, diabetes, and dyslipidemia was associated with a monocyte level below 0.315 k/cumm in a cohort of 15,654 Korean individuals evaluated at the Center for Health Promotion. The highest risk was seen with a monocyte level above 0.411 k/cumm. Researchers note that elevations in both total WBCs and differential counts are associated with an increased risk of metabolic syndrome (Kim 2008). Risk of metabolic syndrome may be lowest in those with a monocyte count of 0.34 k/cumm and highest at 0.59 k/cumm and above (Babio 2013).

Monocytes are thought to play an active role in converting atherosclerotic plaque from stable to unstable, contributing to acute coronary syndrome and impaired blood flow to myocardial tissue (Ghattas 2013). Differentiated macrophages are found within unstable atherosclerotic plaque even if circulating levels of monocytes/macrophages are not elevated (Horne 2005). Vulnerable plaques are more likely to rupture and contribute to thrombosis, stroke, or myocardial infarction. Monocyte-derived macrophages are the most abundant white blood cells observed in atherosclerotic plaque, where they can take up oxidized LDL and other lipids. Monocytes appear to differentiate into foam cells early in the atherosclerotic process, forming fatty streaks within the intima (Woollard 2010). Monocytes play a role in fighting pathogens, removing debris, and promoting tissue repair following myocardial infarction. However, excess production of monocyte-derived cytokines may inhibit the healing process (Dutta 2015).

Optimal vitamin C status can mitigate the adverse effects of monocytes/macrophages on endothelial health. A randomized double-blind crossover study of 40 healthy non-smokers demonstrated that vitamin C supplementation could reduce the adhesion of monocytes to endothelial cells. A dose of 250 mg/day significantly reduced the adhesion of monocytes to endothelial cells by 37% in those with a lower baseline vitamin C of 0.56 mg/dL (32 microM), a level commonly accepted as “normal.” (Woolard 2002). Vitamin C was also found to support endothelial-derived nitric oxide and normalize vascular function in subjects with CVD risk factors, including smoking, hypertension, hypercholesterolemia, hyperhomocysteinemia, and diabetes. Other antioxidants, including vitamin E and thiol antioxidants, are also known to reduce reactive oxygen species and inhibit endothelial activation (Frei 1999).

Examples of thiol antioxidants include glutathione, cysteine, N-acetylcysteine, and alpha lipoic acid (Deneke 2000). Vitamin C supplementation is also recommended during acute and chronic hyperglycemia. Elevated glucose can deplete vitamin C and contribute to cardiovascular risk (Price 2001). This versatile vitamin may also benefit peripheral artery disease, a condition associated with atherosclerosis and elevated CRP. Vitamin C insufficiency may be confirmed by decreased alkaline phosphatase (Langlois 2001).

References

Babio, Nancy et al. “White blood cell counts as risk markers of developing metabolic syndrome and its components in the PREDIMED study.” PloS one vol. 8,3 (2013): e58354. doi:10.1371/journal.pone.0058354

Carlberg, Carsten. “Vitamin D Signaling in the Context of Innate Immunity: Focus on Human Monocytes.” Frontiers in immunology vol. 10 2211. 13 Sep. 2019, doi:10.3389/fimmu.2019.02211

Deneke, S M. “Thiol-based antioxidants.” Current topics in cellular regulation vol. 36 (2000): 151-80. doi:10.1016/s0070-2137(01)80007-8

Deyrup, Andrea T et al. “Essential laboratory tests for medical education.” Academic pathology vol. 9,1 100046. 13 Sep. 2022, doi:10.1016/j.acpath.2022.100046

Dutta, Partha, and Matthias Nahrendorf. “Monocytes in myocardial infarction.”Arteriosclerosis, thrombosis, and vascular biology vol. 35,5 (2015): 1066-70. doi:10.1161/ATVBAHA.114.304652

Frei, B. “On the role of vitamin C and other antioxidants in atherogenesis and vascular dysfunction.” Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.) vol. 222,3 (1999): 196-204. doi:10.1046/j.1525-1373.1999.d01-136.x

Ghattas, Angie et al. “Monocytes in coronary artery disease and atherosclerosis: where are we now?.” Journal of the American College of Cardiology vol. 62,17 (2013): 1541-51. doi:10.1016/j.jacc.2013.07.043

Horne, Benjamin D et al. “Which white blood cell subtypes predict increased cardiovascular risk?.” Journal of the American College of Cardiology vol. 45,10 (2005): 1638-43. doi:10.1016/j.jacc.2005.02.054

Kim, Dong-Jun et al. “The associations of total and differential white blood cell counts with obesity, hypertension, dyslipidemia and glucose intolerance in a Korean population.” Journal of Korean medical science vol. 23,2 (2008): 193-8. doi:10.3346/jkms.2008.23.2.193

Langlois, M et al. “Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis.” Circulation vol. 103,14 (2001): 1863-8. doi:10.1161/01.cir.103.14.1863

Murray, Peter J. “Immune regulation by monocytes.” Seminars in immunology vol. 35 (2018): 12-18. doi:10.1016/j.smim.2017.12.005

Narasimhan, Prakash Babu et al. “Nonclassical Monocytes in Health and Disease.” Annual review of immunology vol. 37 (2019): 439-456. doi:10.1146/annurev-immunol-042617-053119

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Price, K D et al. “Hyperglycemia-induced ascorbic acid deficiency promotes endothelial dysfunction and the development of atherosclerosis.” Atherosclerosis vol. 158,1 (2001): 1-12. doi:10.1016/s0021-9150(01)00569-x

Tigner, Alyssa, et al. “Histology, White Blood Cell.” StatPearls, StatPearls Publishing, 19 November 2021.

Woollard, Kevin J et al. “Effects of oral vitamin C on monocyte: endothelial cell adhesion in healthy subjects.” Biochemical and biophysical research communications vol. 294,5 (2002): 1161-8. doi:10.1016/S0006-291X(02)00603-4

Woollard, Kevin J, and Frederic Geissmann. “Monocytes in atherosclerosis: subsets and functions.” Nature reviews. Cardiology vol. 7,2 (2010): 77-86. doi:10.1038/nrcardio.2009.228

Yu, Jeong Il et al. “Clinical importance of the absolute count of neutrophils, lymphocytes, monocytes, and platelets in newly diagnosed hepatocellular carcinoma.” Scientific reports vol. 11,1 2614. 28 Jan. 2021, doi:10.1038/s41598-021-82177-5

Zorrilla, E P et al. “The relationship of depression and stressors to immunological assays: a meta-analytic review.” Brain, behavior, and immunity vol. 15,3 (2001): 199-226. doi:10.1006/brbi.2000.0597