Week 5 lecture - Exercise, inflammation and the risk of CVD

Question 1

What is inflammation?

Answer 1

Local immune response to physical injury/ damage (cell or tissue), or infection
Characterised by: redness, pain, swelling (heat and loss of function)

Question 2

Functions of inflammation:

Answer 2

1) To destroy infected or damaged tissue (this response is done by phagocytic cells – they engulf the damage)
2) Stimulate tissue repair:
- Cytokines (hormones of the immune system) released by immune cells (in the tissues), endothelial cells and adipocytes stimulate the liver to release acute phase proteins such as C-reactive protein (CRP) and fibrinogen

*key cytokines: T-cell, IL-4, IL-6
*Interleukins are a group of cytokines secreted by immune cells that play important roles in regulating immune responses, including inflammation, cell proliferation, differentiation and activation.

Question 3

When inflammation turns bad… when the repair process isn’t initiated

Answer 3

• Dysfunction of this repair response leads to long-term (chronic) release of inflammatory cytokines by immune cells – leads to ‘Chronic low-grade inflammation’ – a process where the body is constantly producing low level inflammatory cytokines
• Low grade inflammation can stay for months and years

Question 4

Causes of chronic inflammation:

Answer 4

• FFA uptake by immune cells in tissues
• High levels of toxins/ pollutants in the circulation
• Unresolved infection/ autoimmune response (the body produces antibodies against itself)
• Local tissue hypoxia (e.g., in obesity) – tissues have a low level of oxygen so cannot undergo normal metabolic processes
• Inactivity and positive energy balance results in visceral fat accumulation – leading to chronic inflammation

Question 5

Obesity’s link to chronic low grade inflammation:

Answer 5

Adipocyte hypertrophy causes the blood supply to stretch and parts of the adipose tissue don’t get enough o2 – hypoxic areas/ metabolic stress. In response the adipocytes and immune cells start releasing cytokines to indicate stress. This causes an increases in Activated T cells and a movement of M1 macrophages (from the blood)

Question 6

Anti-inflammatory cytokines:

Answer 6

CD4+, T reg Cell

Question 7

Proinflammatory cytokines

Answer 7

Activated T cells
M1 macrophages
IL-6 (main source at rest = adipose tissue)

Question 8

Long-term conditions are associated with chronic inflammation

Answer 8

• Inflammatory bowel disease, stroke, diabetes, lung disease, fatty liver disease, dementias, chronic kidney disease, heart disease, colorectal cancer, endometriosis, inflammatory arthritis.

Question 9

Positive energy balance and physical inactivity:

Answer 9

In conditions of energy excess (positive energy balance) and physical inactivity:

Fat tissue experiences immune cell changes, including the recruitment of M1 macrophages (pro-inflammatory) and activated T cells.
This shift triggers the release of pro-inflammatory adipokines (e.g., IL-6, TNF), increases triglycerides and LDL (low-density lipoprotein), and raises free fatty acids and TLR (Toll-like receptor) expression.
These changes lead to chronic low grade inflammation.

Question 10

The main 2 cytokines that cause IL-6 release

Answer 10

TNF-a and IL-b

Question 11

Biomarkers of chronic inflammation:

Answer 11

1) Stimulus Activation: Factors like injury, infection, high blood lipids, toxins, or tissue hypoxia trigger an inflammatory response.

2) Cellular Response: This stimulus activates endothelial cells (cells lining blood vessels) and other types of cells such as adipocytes and hepatocytes. It also activates immune cells.

3) Cytokine Release: These cells release pro-inflammatory cytokines (such as TNF-α, IL-6, and IL-1β). These cytokines are biomarkers themselves and also signal the body to ramp up inflammation.

4) Liver Response and Acute Phase Proteins: The liver, in response to cytokines like IL-6, produces acute-phase proteins, including C-reactive protein (CRP) and fibrinogen. These proteins are critical biomarkers for chronic inflammation, as elevated levels indicate an ongoing inflammatory state.

Outcome: Elevated levels of these cytokines and acute-phase proteins (e.g., CRP and fibrinogen) serve as measurable indicators, or biomarkers, of chronic inflammation. CRP is offered as a clinical routine test in hospitals.

Question 12

Inflammatory markers across different organs/ tissues:

Answer 12

Liver: Chronic inflammation leads to insulin resistance and the sustained release of acute-phase proteins like C-reactive protein (CRP) and fibrinogen, contributing to systemic inflammation.

Adipose Tissue: Inflammation in fat tissue promotes adipokine production e.g., leptin (pro-inflammatory signals) and immune cell infiltration, contributing to an inflammatory environment.

Brain: Chronic inflammation is linked to the build up of amyloidogenic proteins, as IL-6 can cross the blood brain barrier, which may be associated with neurodegenerative diseases like Alzheimer’s.

Bone: Persistent inflammation affects bone remodelling and can lead to osteoporosis, weakening bone structure. this is because cytokines are highly catabolic

Skeletal Muscle: Inflammation contributes to sarcopenia (muscle loss with aging) and insulin resistance in muscles.

Endothelial Cells: Chronic inflammation causes endothelial dysfunction and arteriosclerosis (hardening of the arteries), raising cardiovascular disease risk.

Question 13

IL-6 Increases with risk factors for CVD in apparently healthy women (Bermudez et al 2002):

Answer 13

• Risk Factors: Age >60 years, Current smoker, Sedentary lifestyle, BMI> 27 kg/m 2 SBP> 140 mmHg Diabetes
• The more of these factors present, the greater the IL-6 response

Question 14

Targetting inflammatory pathways reduces incidence of atherosclerotic disease (Ridker et al 2017):

Answer 14

• > 10,000 patients with previous myocardial infarction and CRP >2 mg/l
• Used monoclonal antibodies (biological medicine) – an antibody to block the production of inflammatory cytokine
• Targeted the IL ‐ 1 β inflammatory pathway (blocks IL-1b being released)
• Found it lowered CRP but not lipid levels (so body mass wasn’t affected)
• Reduced incidence of another event or death after ~4 years (reduced risk by 15% of developing another event or death)
• shows that blocking inflammation has a direct effect on cardiometabolic outcomes

Question 15

Mid lecture summary:

Answer 15

• Acute inflammation is an important immune response to tissue damage
• Chronic inflammation is important in mediating the development and progression of many chronic diseases
• Inflammation is mediated by pro-inflammatory cytokines e.g., TNF-a, IL-6, IL-1B
• IL-6 stimulate the liver to release CRP and fibrinogen
• Elevated pro-inflammatory cytokines, fibrinogen and CRP are associated with increased prevalence of a number of diseases, risk factors for CVD and risk for all-cause mortality.

Question 16

Circulating inflammatory markers decrease with increased amounts of moderate-vigorous activity (Vella et al 2017):

Answer 16

• Biomarker levels (IL-6, TNF-a, CRP, Fibrinogen) decrease as MVPA increase
• Those who had the highest levels of PA also had the smallest waist circumference, lowest subcutaneous fat and visceral fat area
• • Vella found: Significant association between quartiles of MVPA and IL ‐ 6 compared to Q1 and adjusted for subcutaneous and visceral fat area
• The relationship between moderate-vigorous PA and IL-6 can be independent of body fat area

Question 17

Objective physical activity, sedentary time and inflammatory CVD risk markers in middle age British adults (Elhakeem et al 2018):

Answer 17

• Adjusted for covariates including age, socioeconomic status, smoking history, long term health issues, blood pressure, CVD, medications
• For increasing levels of MVPA and LVPA, inflammatory markers (IL-6 and CRP) were lower
• Sedentary behaviour plays an important role – associated with higher levels of inflammatory markers (regardless of PA)
• Inflammatory markers are lower with increased activity and reduced sedentary time
• Fat is a key mediator (losing adipose tissue does play a role)…. But it is not the only mediator. Exercise has an effect regardless of its effect on weight

Question 18

Mechanisms for why long-term PA appears to have an ‘anti-inflammatory’ effect?

Answer 18

1) Decreased amount of adipose tissue:
- Adipose tissue is the biggest source of circulating IL-6 at rest
- By losing fat mass you lose the source of IL-6
- But inflammatory markers are lower even if fat mass isn’t changed, so this cant be the only reason
2) Decreased numbers of inflammatory immune cells infiltrating adipose tissue. The source of IL-6 in the adipose tissue comes from the immune cells
3) Altered cytokine production from inflammatory immune cells
- Exercise causes a decreased production of pro ‐inflammatory cytokines (e.g. TNF‐α, IL ‐ 1 β, IL ‐6)
- Exercise results in an increased production of anti ‐inflammatory cytokines (e.g. IL ‐1ra, IL ‐10)
4) * At higher intensities, skeletal muscle releases of large amounts of pro‐inflammatory IL‐6. This stimulates a counteracting anti‐inflammatory response, whereby IL‐10 is released

Question 19

Migration of immune cells

Answer 19

In obesity adipocytes release inflammatory chemokines to encourage monocytes to leave the circulation and enter adipose tissue

Question 20

Exercise training suppressed inflammatory immune cell infiltration of adipose tissue in mice (Kawanishi et al 2013)

Answer 20

• Inflammatory macrophages per gram of adipose tissue were lower in obese mice who exercised
• In the mice that had a high fat diet but exercise, there was no extra infiltration – exercise minimised immune cell infiltration

Question 20

Does moving more affect immune cell migration (movement) out of the circulation?

Answer 20

People with central obesity (Larger waist circumference) had higher migration of immune cells – immune cells moved towards the tissues suggesting higher levels of chemokines in the tissues
* People with obesity who are active had lower levels of migration than obese sedentary individuals
* Activity helps switch of immune cell migration

Question 21

Regular brisk walking over 6 months by patients with kidney disease lowers inflammatory immune cell activation and release of pro-inflammatory proteins into the blood (Viana et al 2014)

Answer 21

• Pro inflammatory IL-6 decreased and anti-inflammatory IL-10 increased
• Exercise reduced T cells and monocytes (the number of active cells decreased)
• Exercise reduces the likelihood of immune cells releasing cytokines

Question 22

Muscle-derived IL-6 is released during more intense exercise:

Answer 22

• With high intensity/prolonged exercise large amounts in IL ‐ 6 are released from muscle into the circulation.
• This stimulates the release of anti ‐inflammatory cytokines (e.g. IL ‐1ra, IL ‐10) from immune cells in the blood to ‘switch off’ the response
• Regular performance of higher intensity or longer duration exercise can lead to a persistent elevation in levels of IL ‐10 in the blood.

Question 23

End of lecture summary:

Answer 23

• Acute inflammation is a short ‐lasting immune response to tissue damage, characterised by marked temporary, increases in inflammatory cytokines
• Chronic inflammation is a long ‐lasting event, characterised by small, enduring increases in inflammatory cytokines
• Chronic, low level elevations of blood markers of inflammation (TNF‐α , IL ‐ 1 β , IL ‐6, CRP, fibrinogen) are as risk factors for CVD
• Participation in regular exercise is suggested to have ‘anti‐ inflammatory effects’
• Regular physical activity is associated with reduced circulating levels of inflammatory markers at rest
• Regular exercise lowers pro‐inflammatory cytokine release from immune cells at rest
• Higher intensity exercise causes acute large increases in IL‐6 from muscle that are countered by the release of anti‐ inflammatory cytokines