Low-Grade Systemic Inflammation

The root of all evil?

Inflammation
Acute
Chronic
Inflammation is a normal defense mechanism that protects the host from
infection and other insults.
It initiates pathogen killing, tissue repair processes and helps restore
homeostasis at infected or damaged sites.
It is typified by redness, swelling, heat, pain and loss of function.
It also involves interactions amongst many cell types and the production of,
and responses to, a number of chemical mediators.

A typical inflammatory response involves four major events:

1. An increased blood flow to the site of inflammation
2. Increased capillary permeability caused by retraction of endothelial cells.
This allows larger molecules to cross the endothelium and deliver soluble
mediators at the site of inflammation.
3. Leukocyte migration from the capillaries into the surrounding tissue. This
is caused by the chemo-attractants released at the site of inflammation.
4. Leukocytes release mediators such as prostaglandins, leukotrienes,
cytokines, histamine, reactive oxygen species at the site of inflammation.

Essential fatty acids synthesis

Palmitate 16:0

Stearate 18:0

Oleate 18:1

Linoleate 18:2

-linolenate
18:3

-linolenate 18:3
Eicosatrienoate 20:3
Arachidonate 20:4

Other PUFA
Prostaglandins Thromboxanes

Leukotrienes

Lipoxins

Synthesis of -3 and -6 polyunsaturated fatty acids

DHA Docosahexaenoic acid (22:6); EPA Eicosapentaenoic acid (20:5)

Mechanisms by which PUFA can influence inflammatory cell function:

Dietary PUFA profile can influence complex lipid, lipoprotein, metabolite
and hormone concentrations that in turn influence inflammation.
Non-esterified PUFA can act directly on inflammatory cells via surface
and/or intracellular fatty acid receptors such as peroxisome proliferator
activated receptors.
The oxidized esterified and non-esterified PUFA derivatives can act directly
on inflammatory cells via surface or intracellular receptors.
PUFA can be incorporated into the membrane phospholipids of inflammatory
cells where they exert important roles such as assuring the correct
environment for membrane protein function, membrane fluidity and raft
formation.

The Obesity Epidemic: Consequences for public health

Premature aging and death

Type 2 diabetes

Cancer

Fatty liver disease

Osteoarthritis

Atherosclerosis

Obesity

Hypertension

Neurodegeneration
Kidney disease

Stroke

Metabolic disorders cluster

What is low-grade systemic inflammation?

Clinically, low-grade systemic inflammation is defined as a 2 to 4-fold
elevation in circulating levels of pro-inflammatory and anti-inflammatory
cytokines and other markers of immune system activity.
Chronic, low-grade systemic inflammation often does not have symptoms.
It is long-term and occurs in wear and tear conditions such as obesity,
diabetes, autoimmune disorders, heart disease and others.
Chronic inflammation is characterized by infiltration of the affected tissue by
mononuclear cells, angiogenesis, destruction of the affected tissue and
subsequent healing by replacement of the damaged tissue through fibrosis.
Visceral obesity appears to involve all the features of chronic inflammation.

Succinate acts as a signal molecule in response to the activation of macrophages by

lipopolysaccharides (LPS).

Source: J. Biological Chemistry 288, 22893-22898 (2013) How metabolism

generates signals during innate immunity and inflammation.

NAD+ , AMPK and SIRT1 are key inflammatory regulators in

conditions such as gout and atherosclerosis

Source: J. Biological Chemistry 288, 22893-22898 (2013)

How metabolism generates signals during innate immunity
and inflammation.

Adipose tissue obesity is a chronic inflammatory disease

Endocrine, inflammatory, and neuronal pathways link obesity to insulin resistance.

Mohammed Qatanani, and Mitchell A. Lazar Genes Dev.

2007;21:1443-1455
Copyright 2007, Cold Spring Harbor Laboratory Press

A high-fructose and high-fat diet lead to low-grade systemic inflammation and

metabolic syndrome

Cell signaling pathways triggered by insulin and insulin-like growth factor 1

Adipose tissue inflammation and atherosclerosis exhibit common features

Adipose tissue

Coronary blood vessels

Activation of leukocyte adhesion

cascade

Activation of leukocyte adhesion

cascade

Angiogenesis promoted by IL-6

and TNF-

Angiogenesis

Cellular interactions between

resident cells and macrophages

Cellular interactions between cells

within arterial wall and macrophages

Dynamic changes in the

organization of adipose tissue
architecture (tissue remodeling)

Dynamic changes in the organization

of arterial wall architecture formation
of the atherosclerotic plaque

Adipokine secretion by adipose tissue in insulin-resistant obese subjects

Inflammation and cancer

Hyperinsulinemia, obesity and hypoxia are linked to inflammation and cancer
development. Cytokines such as IL-6 and TNF- are considered to form one link
between inflammation and cancer.
Cancer causing mechanisms like loss of tumor suppressor function, increase of
cell cycling and stimulation of oncogene expression were found to be related to
cytokines, ROS and mediators of the inflammatory pathways (TNF- and COX-2).
Chronic inflammatory disorders increase the risk of cancer development in some
organs such as GI tract, thyroid gland, prostate, pancreas, urinary bladder and
others. However, the critical role of inflammatory cells in cancers that can not be
linked to a pre-existing inflammatory condition has been recognized only recently.

Mechanisms of intestinal inflammation-mediated carcinogenesis

Source: Mutation Research 705(1) 40-59 (2010)

Diet and inflammation

I. Foods that cause inflammation
1. Monosaccharides (glucose, fructose) in table sugar and HFCS
A high sugar intake leads to:
Obesity, inflammation and metabolic syndrome
Increased blood uric acid levels that in turn causes inflammatory
responses
Release of pro-inflammatory cytokines from endothelial cells
2. Trans fatty acids
Trans fatty acids are present in partially hydrogenated oils (margarine)
are known to increase to blood levels of pro-inflammatory cytokines
such as IL-6, TNF- and also the level of circulating C-reactive protein.
There is a direct link between the consumption of trans fats and heart
disease.

3. Vegetable oils
These oils come from the corn, sunflower and soybean seeds. Due to
their high content of -6 PUFA these oils promote low-grade systemic
inflammation, which in the long run lead to metabolic syndrome.
4. Excessive alcohol consumption
A high alcohol consumption leads to:
Liver cirrhosis
Increased plasma CRP and low-grade systemic inflammation
Leaky gut syndrome
5. Processed meat
Common types of processed meat include sausages, ham, bacon and
smoked meat. A high consumption of processed meat is associated with
increased risk of heart disease, diabetes, stomach and colon cancer.
Processed meat, including the widely popular barbeques contain a high
level of advanced glycation end products. These product are formed as a
result of the reaction between simple sugars and amino acid residues in
proteins under conditions of high temperature.

II. Anti-inflammatory foods

1. Cold-water fish (salmon, herring, tuna, mackerel). 300-350 g per week.
Fish should be cooked by boiling or baking, NOT fried or dried/salted.
2. Avocados. They contain oleic acid, -linolenic acid, vitamins B1, B2, B5,
B6, K, E, C, folate, fiber and the minerals copper, magnesium,
potassium and iron. A 2013 study in the journal Food and Function
found that people who ate a hamburger with avocado had lower CRP
levels four hours after eating than those who did not.
3. Broccoli and other cruciferous vegetables. These vegetables contain
sulforaphane (an organosulfur compound), which may have antiinflammatory activity as well as antibacterial activity against H. pylori.
4. 4. Water melon. Rich in vitamin C, lycopene an inhibitor for various
inflammatory processes. Some of the possible mechanisms of lycopene
action include scavenging of free radicals, inhibition of pro-inflammatory
cytokines, alterations of eicosanoid synthesis and modulation of signal
transduction pathways involving NF-B, AP-1 and MAPK signaling.
Lycopene may also exhibit anti-inflammatory activity through induction of
apoptosis in activated immune cells.
5. Onions. Good source of quercetin, which is an antioxidant and antiinflammatory flavonoid. Quercetin has been shown to inhibit proinflammatory prostaglandins through the inhibition of the enzyme 5lipoxygenase. Also, the flavonoids in onion and garlic were able to

reduce inflammation in animals that developed insulin resistance after a highfructose diet.
6. Berries (blackberry, strawberries, blue berries, black courant). Polyphenols
such as anthocyanins, present in these fruits were shown to reduce
inflammation in animal experiments as well as in some human studies.
7. Whole grains (wheat, brown rice). Consumption of these foods reduces the
plasma level of CRP. The fiber in whole grains helps mediate inflammatory
processes and favors the growth of beneficial bacteria in the gut.
8. Fermented foods and yogurts such as kefir.
9. Spices. Ginger, rosemary, curcumin, oregano, cloves, cayenne and others
possess anti-inflammatory properties.
III. Foods to avoid
Avoid refined sugars and processed foods. Cut back on red meat and full-fat
dairy products. Avoid beverages with high alcohol concentration.

The anti-inflammatory food pyramid

In health matters be proactive, not reactive!