What actually is inflammation?!
To listen to this blog post instead, check out episode 2 of Osha Health: The Podcast.
Inflammation is implicated in almost every disease state or health struggle.
Inflammation is one way that your immune system responds to various types of threats to your survival or health. Some of these harmful things can be pathogens (like bacteria or viruses), external tissue injuries and internal cellular damage, and toxic compounds (like chemicals and heavy metals). When something harmful is present, your immune system enlists its ability to create inflammation to fight against these things, protect you and attempt to heal from the damage.
What is involved in inflammation?
Your cells have sensors on them (called pattern-recognition receptors, or PRRs) and these sensors are able to detect things like the presence of pathogens (by recognising PAMPs), cell damage (by recognising DAMPs) or chemicals that shouldn’t be there. When they are alerted to these things, your cells can produce compounds such as cytokines, chemokines, vasoactive amines and eicosanoids which are chemical messages; basically the message is “Danger! Attack!”. These messages can travel to a tissue and attach to receptors on cells there, and cause a cascade of events to eliminate whatever the problem is. This is the inflammatory part. Intracellular signaling pathways (such as NF-kB, MAPK and JAK-STAT) are activated and these pathways result in lots of downstream effects which can change how a cell functions and trigger it to produce cytokines and other compounds to enhance the inflammatory process.
This will look different depending on what the initial trigger is, for example:
The T cells and natural killer (NK) cells in your immune system have sensors called toll-like receptors (TLRs). If these sensors sense the presence of a virus, this will cause the immune cell to release a mediator called interferon, which interferes with that virus’ ability to replicate.
If the TLRs sense a bacteria, the cell will produce mediators like TNF-alpha, interleukin-1, interleukin-6, histamine and prostaglandins – these mediators then act on various tissues to dilate your blood vessels and make them a bit leaky, to bring blood flow to the area and to recruit lots of white blood cells to the area so that they can fight that bacteria. If the cell has been infected, or the DNA has been damaged and it has become cancerous, the release of TNF-alpha signals that the cell itself needs to be destroyed.
If a cell is under threat, it will release some of its ATP and/or mitochondrial DNA. When this ATP and DNA is outside of the place where it is normally meant to be, this is telling the body that something is wrong. The TLR9 receptor is activated by these fragments and this induces inflammation. The mitochondria also change their metabolism which causes a lot of reactive oxygen species inside the cell which is damaging and thus inflammatory too. The mitochondria will do this if they sense that a pathogen has invaded the cell, but also in the presence of chemicals, heavy metals and endotoxins. (This is part of the Cell Danger Response.)
Ending inflammation
Once whatever was threatening us has been eliminated, the mediators switch from being pro-inflammatory to pro-resolution. Pro-resolution mediators cause different things to happen. The production of inflammatory cytokines decreases and healing processes are promoted. The white blood cells undergo apoptosis meaning they are destroyed and engulfed by other immune cells called macrophages, which then leave the area via your lymphatic system. Your blood vessels return to their prior state, your connective tissue is healed from any collateral damage and your cells go back to their regular methods of functioning.
So, inflammation is beneficial, it’s necessary and it is your body protecting you from harm… which is good! Without it, a simple injury or infection could eventually be deadly. The problem is when the process of inflammation persists for too long. This can happen for 2 main reasons: if your immune system is continuously being activated by the presence of something harmful, or if you are unable to effectively undergo the pro-resolution phase which is needed for inflammation to end.
Continuous activation of the immune system can occur due to:
an ongoing infection that you were not able to completely neutralise and eliminate, eg. latent infections like Epstein Barr Virus (EBV, which is associated with glandular fever), Borrelia (which is associated with Lyme disease) or oral dysbiosis (P. gingivalis is largely responsible for gingivitis which is chronic inflammation in the gums).
environmental pollutants such as air pollution, chemicals, pesticides, heavy metals
exposure to mould and other allergens
a condition called Chronic Inflammatory Response Syndrome (CIRS) and subsets including Mast Cell Activation Syndrome (MCAS)
regularly eating foods that you are sensitive to
What does it mean to not properly go through the resolution phase of your inflammation? The inflammatory processes don’t just sort of wind down and stop once there is not a need for them anymore. There are several ways that the body actively switches inflammation off:
One way is through the Nrf2 pathway, which regulates the expression of anti-inflammatory genes and inhibits inflammation from progressing. It interrupts the cycle of oxidative stress activating inflammatory pathways which leads to the production of cytokines, which causes more oxidative stress. It suppresses COX-2, TNF-a and IL-1B.
We need to produce a type of fatty acid called a specialised pro-resolving mediator (SPM) as well as certain interleukins and other compounds such as annexin A1, adenosine and inosine. These molecules will turn down the inflammation by programming macrophages (which are a type of white blood cell) to change from their M1 form (which produce lots of inflammatory cytokines) into their M2 form (which is anti-inflammatory and which clean up the dead pathogens and dead immune cells like a pac man; they literally engulf the inflammatory debris in a process called phagocytosis). The M2 macrophages send out signals that are anti-inflammatory in nature (such as interleukin-10 and TGF-beta) and then we need them to leave the area by draining into the lymph. This all needs to happen so that the tissues can return to their pre-inflammatory state.
Note: This is NOT the same as anti-inflammatory drugs or supplements that BLOCK inflammation. By blocking inflammation from moving through its steps, you are actually preventing the opportunity for the resolution stage to eventually kick in. A study of ibuprofen (Advil) showed that it blocked the formation of inflammatory mediators as you would expect, but it also blocked the inflammation-resolving compounds too. These kinds of medications are prioritising quick relief from pain, but at the expense of proper healing and recovery.
There are different categories of SPMs including resolvins, protectins and lipoxins. SPMs are made from polyunsaturated fats, specifically EPA and DHA found in oily fish and fish oil, and the SPM lipoxin is actually made from arachidonic acid which is found in red meat. If you don’t eat these foods, our bodies can make small amounts of them from nuts and seeds that we eat, although this is heavily variable according to our genetics.
How do these SPMs actually resolve the inflammatory process? Some bind to neutrophils and prevent them from releasing TNF-alpha and interferon-gamma, which are 2 of our inflammatory cytokines. They can block the action of histamine so that it no longer contributes to allergic symptoms. They may also bind to stem cells in muscles and periodontal ligaments in the mouth to regenerate damaged tissue.
What are the sources of inflammation?
Physical – this can include injuries, burns, radiation, excessive exercise, chronic infections, poor posture, lack of sleep, obesity, dysregulated immune response (such as autoimmune conditions)
Nutritional – processed foods, chronically high blood sugar, alcohol, dysbiosis, gluten, food sensitivities, intestinal permeability
Environmental – chemicals in foods, pesticides, conventional personal care products, medications, air pollution, mould, heavy metals, smoking. These alter many molecular pathways, and not for the better. They can cause oxidative stress in our cells, which damages DNA and triggers inflammatory pathways to be activated. Urban air pollution causes the production of reactive oxygen species within mitochondria in the lungs and a subsequent release of IL-6.
Emotional – psychological stress, trauma. This affects people very differently, but key inflammatory pathways become activated (including nuclear factor-kB and subsequent increases in interleukin-6 and other cytokines) and our genetic expression can be altered.
Layering on top of that, we are all unique in our genetics which make us either more susceptible to or more resilient to potential sources of inflammation.
Here are more details on some of the above factors:
What is it about our modern diet that is inflammatory? Processed foods often spike our blood sugar, which can damage our blood vessels and indeed our organs through a process called glycation, which then triggers an inflammatory response to fix it. Many fried foods contain oxidised fatty acids which trigger macrophages which release inflammatory cytokines, and they also contain AGEs (Advanced Glycation End Products) which activate NF-kB. In addition, they can alter the balance of bacteria in the gut leading to a more pro-inflammatory state, and these foods are often largely devoid of nutrients and antioxidant compounds that would help us to mitigate the inflammation that is being caused.
How is obesity a source of inflammation? Fat cells, especially visceral fat cells (ie. those around your middle) produce their own cytokines (including TNF-a, plasminogen activator inhibitor-1, several interleukins, CRP, and leptin and many more), and there are macrophages and lymphocytes in the fat tissue that are chronically activated by these inflammatory compounds, thus producing a chronic, low-level inflammatory state. The dysregulation of metabolism that is happening in these cells that are struggling to cope with the excess of energy further leads to inflammatory processes. This is especially problematic because research has shown that when adipocytes are exposed to inflammatory cytokines (which they not only are exposed to from systemic inflammation but from the inflammation they themselves are generating), there are kinases in the cells which cause changes in those fat cells to both impair insulin sensitivity (which leads to chronically high blood sugar, which is inflammatory) and contribute to the expression of pro-inflammatory genes (through activation of AP-1 (activator protein-1 complexes) and NFkB).
A lack of sleep increases inflammation because it impairs our ability to manage our blood sugar, and hormones including melatonin (which are highest when we are asleep) modulate our immune system during the REM stage of sleep.
Exercise modulates our immune system and releases endorphins which are anti-inflammatory in nature, but it is possible to overdo it, which is termed “metabolic overtraining syndrome” and this is a situation of excessive exercise leading to damage which is inflammatory.
Is inflammation an issue for you?
Over time, the body’s inflammatory response can start damaging healthy cells, tissues, and organs. For this reason, chronic inflammation has been associated with many diseases and health conditions including heart disease, cancer, obesity, type 2 diabetes, asthma, depression (particularly in depression that is not responsive to drug treatment), chronic pain, dementia and Alzheimer’s disease, autoimmune diseases including rheumatoid arthritis and Celiac disease, headaches and migraines.
As well as these overt diagnoses, the symptoms of chronic inflammation can be extremely variable. It might present as pain in the muscles or joints; fatigue that is unrelenting; brain fog; sleep problems; weight gain or weight loss; injuries that just won’t heal; various digestive issues and issues with fertility. There is also a so-called “sickness syndrome” where exposure to pro-inflammatory cytokines produces a syndrome with symptoms that overlap considerably with those seen in depression, as in low mood, lack of appetite, disrupted sleep and loss of pleasure in everyday activities. The parts of the body that will be primarily affected depends on what the source of the inflammation is, and on your own predisposition to developing certain issues.
We all have some amount of inflammation present throughout our body all of the time but if you have any of the conditions or symptoms above, or if any of the sources I mentioned stand out for you, it might be something to consider addressing. In terms of testing, a CRP level (which is most commonly what a doctor will check) that is higher than 3mg/L is considered high. However, CRP is only one of about 180 known inflammatory markers. Different markers are triggered by different sources of inflammation and they can give you a more specific insight into what might be going on for you. In Australia, Nutripath offers a cytokine panel which tests a variety of pro- and anti-inflammatory cytokines in the blood. There are a few extra markers that can be tested through US labs. Various tissue-specific antibodies would also give us a clue, as would symptoms. There is no one marker, it is the whole picture so this is where working with a practitioner would be ideal.
What can you do?
If you know or suspect you have chronic inflammation and you want to do something about it, your intention should be to address your unique cause of inflammation, by choosing strategies that apply to what is going on for you, as well as taking a systemic perspective by applying more general principles. This is where working with a practitioner is incredibly helpful. Keep in mind that addressing inflammation from multiple angles is the most effective strategy. Using NSAIDs or corticosteroids to manage inflammation have their place but can be damaging in the long term, so here is some naturopathic advice.
Diet
The foods we eat can create or worsen inflammation, or reduce inflammation and promote an internal environment where less inflammatory damage is occurring. In general, a diet high in vegetables and fruit, with minimal processed foods, in line with a dietary pattern such as the Mediterranean diet is associated with decreased levels of inflammatory biomarkers (mainly CRP, IL-6 and TNF-a) and a lower incidence of chronic disease, while a diet high in ultra-processed foods more in line with a typical Western diet is associated with higher levels of these inflammatory biomarkers.
This is because the phytochemicals in the fruits and vegetables, and the EPA and DHA present in fish and available to us in a lower amount when we consume nuts and seeds, provide us with a buffer against low-grade inflammation. Eating a variety of brightly coloured fruits and vegetables will provide an array of compounds that modulate inflammation, and herbs and spices are particularly rich sources of these beneficial compounds. We want to minimise refined carbohydrates, deep fried foods, processed meats and artificial additives; really anything we would consider junk food.
Pro-resolving mediators (SPMs)
I would add that eating fish and red meat (ideally grass-fed), and to a lesser extent eggs (especially those labelled as high omega-3 eggs) is important to get EPA, DHA and arachidonic acid which provide the building blocks for us to produce pro-resolving mediators. You might remember that pro-resolving mediators are what we need to turn off the inflammatory response. We can produce them from compounds in fish and red meat, and to a lesser extent eggs, and to an even lesser extent nuts and seeds. Many people have difficulties with this conversion process for genetic reasons or due to nutritional deficiencies, so to get a higher amount of these compounds you can supplement with fish oil, or vegans can supplement with algae oil. Whatever form you buy, make sure to check the label for the amount of EPA and DHA that you will be getting as the amounts can vary A LOT between products. You want to aim for at least 2000mg of EPA and DHA together. Krill oil often doesn’t have a fishy aftertaste which may be desirable if you are having to take a high dose. There are also SPM supplements on the market which include EPA and DHA and several intermediaries to help you make the conversion. They are helpful but expensive. A dose of at least 3 grams will significantly increase SPM levels for 2-6 hours after supplementation. And I would recommend taking it in the morning, as our natural production of SPMs follows a circadian rhythm, being highest in the morning then fading throughout the day. So taking your dose in the morning would mimic this natural flow.
Here's a little hack: Your own synthesis of SPMs increases in the presence of hypoxia, or lack of oxygen. This is because hypoxia is often a result of inflamed tissues, which is a situation when you would want SPMs. Hypoxia isn’t a good thing to have long-term, but in the short-term for this purpose, one way that you can cause intermittent hypoxia is through Wim Hof breathing.
Foods and supplements to focus on (aka heavy hitters that will target lots of different inflammatory pathways)
Turmeric: not a magic bullet for everyone, however turmeric and a main compound curcumin has been shown to reduce CRP, TNF, IL-1B, IL-4, IL-6, LOX, COX-1 and COX-2. In a RCT of patients with metabolic syndrome, taking 1 gram of curcuminoids with 10mg piperine reduced serum levels of CRP.
Quercetin: as an antioxidant, quercetin scavenges free radicals which would otherwise promote inflammation. It reduces TNF, IL-6, IL-8, 5-LOX, COX and it has been shown that just one day of supplementation improves the balance between pro- and anti-inflammatory compounds. Some of the best sources of quercetin are apples, grapes and red onions.
Polyphenols: modulate many different cytokines and inflammatory pathways. Polyphenols are present in high amounts in berries, apples, cocoa and green tea. A key polyphenol in green tea is called EGCG (epigallocatechin gallate). EGCG can modulate inflammation in our cardiovascular system due to excess glucose, and it reduces COX-2 by inhibiting IL1B, blocks Nf-kB activation and supports the Nrf2 pathway.
Support the Nrf2 pathway: it increases glutathione and suppresses COX-2, TNF-a, IL-1B, IL-6, Th-17, MMP-9 and MMP-7. Plants are very rich sources of compounds that activate Nrf2; some of the best-researched compounds include: curcumin (turmeric), sulfurophane (broccoli sprouts), anthocyanins (berries, grapes and grapeseed extract), EGCG (green tea), alpha lipoic acid, resveratrol (grapes), lycopene (tomatoes), zeaxanthin and lutein (leafy greens and egg yolks), astaxanthin (seafood), silymarin (milk thistle) and rosmarinic acid (rosemary, basil and tulsi).
PEA (phenylethanolamide): this compound is naturally produced by our body and has been shown to downregulate the release of inflammatory mediators from mast cells and other immune cells.
Herbal medicine
Like foods, herbs contain hundreds of different compounds so the more you ingest, the more pathways in the body that you will be targeting to bring inflammation down. A lot of the herbs we consider to be anti-inflammatories provide us with antioxidants, downregulate the Nf-KB pathway and help to heal tissues.
Some herbs, such as willow bark and meadowsweet, contain salicylates which inhibit the COX pathway. Ginger inhibits this pathway too. This makes them particularly useful for reducing the pain of osteoarthritis. Whereas in a condition like lupus, which is more about an excess of leukotrienes and NF-kB, willow may not be as useful but turmeric may be very helpful. Boswellia, Bupleurum and Baical skullcap are other herbs with far-reaching anti-inflammatory activity.
A fun fact about the usefulness of flavonoids: Flavonoids are ubiquitous in fruits, vegetables and herbs and are known to be antioxidant and anti-inflammatory. When neutrophils and macrophages infiltrate tissues during the inflammatory process, they release an enzyme called betaglucuronidase. This enzyme cleaves flavonoids from the conjugates they are attached to, which converts them into their activated form. This means that these helpful flavonoids have their helpful effect at the places in the body where they are needed.
Adaptogens can reduce inflammation by reducing the impact of stress and oxidation on our tissues, which are themselves factors that contribute to inflammation.
Lifestyle advice
Look to address some of the sources of inflammation that I mentioned earlier:
Maintain a healthy weight
Exercise a moderate amount, but don’t overdo it
Minimise your exposure to radiation
Minimise your alcohol consumption
Keep your stress levels low as much as possible!
Minimise your exposure to chemicals in your food, water, air and personal care products
Prioritise sleep. Sleep is when our body goes into repair mode so if we shorten this window of time, more cellular damage will remain, which is a trigger for inflammation. Also, TNF levels slowly increase throughout the day, peaking before sleep and melatonin appears to inhibit TNF. If sleep deprivation occurs, TNF continues to elevate which means more inflammation. And, lack of sleep has been shown to cause increased oxidative stress in the gut, which directly increases inflammatory cytokines. So, in addition to regular good sleep hygiene practices, if you know you are going to be missing out on some sleep for some reason, consider taking antioxidants like NAC or alpha lipoic acid which will have systemic benefits. A gut-healing herbal tea in the morning and ideally the night before can help offset this too.
In addition,
Try intermittent fasting. It switches on anti-inflammatory pathways including mTOR.
Spend time in nature. We know intuitively that we feel better when we spend time outside, but many studies confirm that being in nature regulates our immune system and hormones to lower inflammation.
Find ways to incorporate more joy, contentment and awe into your life. A 2015 study showed that these emotions were correlated with reduced levels of interleukin-6 in the body, and it was awe that had the most dramatic correlation.
From what we eat, to supplements and herbs we might choose, to lifestyle choices, there is a lot that can be done to address the level of inflammation in our body. Nevertheless, I encourage you again to seek out a practitioner if you are feeling stuck!
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