Monocytes, Macrophages and Dendritic Cells
Monocytes make up a relatively small proportion of circulating leukocytes (2-12 %) but due to their diverse role in immune function and inflammation have received more interest in the exercise literature than neutrophils. With age, there is a tendency for monocytes to adopt a pro-inflammatory phenotype as characterized by increased expression of CD16 and synthesis of TNFa, IL-6 and IL-ip in the basal state [26, 27]. However, they and their differentiated forms, macrophages and dendritic cells, are less functional as characterized by reduced TLR stimulation, cytokine production and antigen presentation upon stimulation [28, 29]. Together, dysfunctional monocytes are associated with the pathogenesis of inflammatory diseases such as CVD and peripheral artery disease . Exercise may serve as a tool to reduce the inflammatory nature of monocytes and macrophages .
In response to acute short bouts of exercise such as running and cycling, peripheral monocyte numbers are increased. The pro-inflammatory CD16+ population accounts for the largest percentage change and is likely indicative of a surveillance mechanism . Although following acute exercise the numbers and percentages of subtype’s return to basal levels there is a marked reduction in CD16+ monocytes after exercise training interventions [32,33]. It is unclear whether the repeated exercise sessions of training is removing CD16i monocytes from the circulation or whether the differentiation to a CD16+ monocyte is perturbed in relation to changes in inflammation, metabolism and endocrine mediators. Timmerman and colleagues showed that older active individuals had lower percentages of CD16+ monocytes than inactive age and sex matched individuals . Following 12-weeks of aerobic exercise at 70-80 % of heart rate reserve combined with resistance exercise the inactive individuals reduced the total percentage of CD16+ monocytes . Recently, resistance training with no weight loss was sufficient to reduce the CD16+ population . Thus, both aerobic and resistance training have been shown to influence CD16+ monocyte numbers, highlighting these cells as potential exercise-mediated inflammatory biomarkers of disease risk.
In addition to reduced CD16 expression, 12-weeks of combined aerobic and resistance training was sufficient to reduce basal and LPS stimulated TNFa production . Although TLR-4 expression was unaffected by training and the inflammatory response likely due to the reduced percentage of CD16I cells, others have shown lowered TLR-4 and TLR-2 expression with training in the elderly [31, 35, 36] . Following prolonged acute exercise TLR expression is reduced for several hours. Mechanisms behind the exercise induced reduction in TLR expression are unknown however it has been suggested that anti-inflammatory cytokines and/or glucocorticoid production may have an impact . Additionally, 12-weeks of a combined resistance and aerobic exercise intervention resulted in an increase in expression of the co-stimulatory molecule CD80 . Reduced expression of CD80 on monocytes has been shown to relate to poor vaccine responses in the old due to reduced activation potential of T-cells and antigen presentation capabilities . Phagocytosis of pathogens is reduced with ageing however the effects of exercise have received little attention. To date the only study to assess phagocytosis was in middle aged men and showed no changes following 12 weeks of training .
Migration of peripheral blood monocytes and their subsequent differentiation to macrophages in adipose tissue is critical to the development of sustained inflammation during obesity. Whether exercise can moderate this process and reduce inflammation is unknown. Although it is unclear if exercise or the negative energy balance associated with exercise reduces adipocyte mass, the production of chemokines (MIP1a and MCP-1) responsible for macrophage infiltration is reduced with exercise . Vascular adhesion molecules such as ICAM-1 are increased with ageing and chronic disease but have been shown to be reduced by 6 months of aerobic exercise . Therefore it is plausible that exercise reduces the migratory capacity of monocytes into adipose tissue . Macrophages with the inflammatory phenotype (M1) are preferentially associated with increased adipose tissue . The effects of exercise on macrophage phenotype in humans remains to be determined, however in mice it has been recently suggested that exercise induces a phenotypic switch of M1 to anti-inflammatory/regulatory M2 macrophages in the adipose tissue as well as reducing M1 infiltration .
Few studies have assessed the relationship of exercise and dendritic cell (DC) function. Similar to monocytes, DCs with age exhibit an increased pro-inflammatory phenotype and reduced antigen presenting capacity [28, 45]. Recently, a single bout of acute exercise was sufficient to increase numbers of monocyte derived DCs without compromising function . Therefore, in those with compromised DC function it is plausible that exercise can facilitate generation of more DCs and at least maintain DC function. In individuals with non-small cell lung cancer, 8-weeks of tai chi classes was sufficient to increase numbers of myeloid DCs in the blood, potentially providing enhanced immunity against cancer . Both myeloid and plasmacytoid DC’s are mobilized by acute exercise with myeloid DC’s increasing to a greater extent . Given the importance of DC function in relation to health and disease risk, more research is needed to determine the role of exercise on DC function.
Taken together, it is clear that exercise and physical activity have an impact on monocytes, macrophages and dendritic cells. Although obtaining tissue resident macrophages and DCs is a laborious, expensive and highly invasive task in relation to exercise, the generation of these cells from exercise modified blood monocytes will provide greatly needed insight to the functions of such critical immunologic and inflammatory mediators.