TWIK2 channel mediates inflammation, study finds


View:410 Time:2018-06-28


Novel way to control inflammation

A new study has identified a potential target for anti-inflammatory therapies. The study was carried out by scientists from the University of Illinois College of Medicine and St. Jude Children's Research Hospital, and its main discovery was that the potassium efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation[1].

Inflammation has both beneficial and harmful effects on the body. It's an important part of immunity, helping kill an invading bacterium or virus, and required for tissue debris clearance, wound healing and tissue repair. However, inflammation can also be misdirected, causing tissue damage, and is considered as the root cause of many diseases, including cancer.

Previous studies have established that inflammation involves the activation of inflammasome, which is a macromolecular cytosolic protein complex in immune cells. Inflammasome is activated in response to various stimuli, such as the efflux of potassium ions across the cell membrane. But the identity of the potassium efflux channel has remained elusive.

In the current study, scientists identified that the channel is TWIK2. They examined the function of WIK2 in macrophages, using a mouse model of sepsis (systemic inflammatory response syndrome). Macrophages are a group of immune cells responsible for detecting, engulfing and destroying pathogens and apoptotic cells, and macrophage infiltration is a hallmark of inflammation. Scientists found that deletion of Kcnk6 (encoding TWIK2) prevented the activation of the NLRP3 inflammasome in macrophages and suppressed sepsis-induced lung inflammation. Inflammatory lung injury was prevented by TWIK2 loss in macrophages.

These data reveal that TWIK2 is the potassium efflux channel that plays a key role in inflammasome activation. Thus, targeting TWIK2 might be a way to control excessive inflammation. Currently, there are drugs available to target potassium channels. But more research is needed to develop drugs specific to TWIK2. Besides, many of the currently used anti-inflammatory drugs cause adverse effects. A better understanding of inflammatory responses would facilitate the development of less toxic anti-inflammatory drugs.

The study "opens up the possibility of developing targeted new anti-inflammatory drugs to modify its function and help and reduce inflammation," according to senior author of the study Dr. Asrar Malik at the University of Illinois College of Medicine.

Quinine is a natural product extracted from plants, and has an antimalarial effect. It is used as a medication to treat malaria and babesiosis.

Jalees Rehman from the University of Illinois College of Medicine, who also participated in the study, believed that the fever-suppressing effect of quinine may correlate with its effect on the TWIK2 channel. Rehman pointed out that quinine decreases the levels of IL-1β, an inflammatory cytokine known to trigger fever.

Findings of their study have been summarized in a paper titled "The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation," appearing in Immunity.


Overview of Inflammation

Generally speaking, inflammation is the body's immune system's response to stimuli. It's considered as a part of innate immunity, as compared to adaptive immunity. Inflammation happens when the immune system fights against something that may turn out to be harmful. Many immune cells, molecular mediators, as well as blood vessels play a role in an inflammatory response.

Inflammation is beneficial in that it fights off foreign invaders, heals injuries and clear debris. Without inflammation, wounds would fester, leading to progressive tissue destruction, and infections could become deadly. However, inflammation can also be bad that it may lead to many chronic diseases, such as arthritis, asthma, atherosclerosis, blindness, cancer, diabetes and mental illness. Therefore, inflammation is normally tightly regulated by the body.


Cause of Inflammation

Inflammation has a number of causes, including:

1. Infection by pathogens like bacteria, viruses or fungi
2. Injury like cuts, scrapes, burns, frostbite, penetrating, and trauma
3. Certain diseases or conditions
4. Foreign bodies like splinters, dirt, and debris
5. Effects of radiation
6. Exposure to chemical irritants or toxins
7. Consumption of alcohol[2]
8. Stress and certain emotions such as anger, frustration, depression, and excitement
9. Lack of sleep[3]
10. Diet high in sugar and processed foods
11. Lack of exercise
12. Obesity
...

There are a large number of diseases that cause inflammation. These diseases often have a name ending in "-itis." Some examples include appendicitis (inflammation of the appendix), cystitis (inflammation of the bladder), dermatitis (inflammation of the skin), encephalitis (inflammation of the brain), gingivitis (inflammation of the gums), nephritis (inflammation of the kidneys), and neuritis (inflammation of a nerve).


Sign of Inflammation

Symptoms of inflammation vary depending on whether it is acute or chronic. There are five signs that may indicate an acute inflammation:

1. Redness
2. Heat
3. Swelling
4. Pain
5. Loss of function

If inflammation occurs in the skin, the five signs may appear. But if inflammation occurs deep inside the body, only some of the signs may be noticeable. Some of these indicators are also seen in an allergic reaction.

Symptoms of chronic inflammation present in a different way. These can include:

1. Fatigue/loss of energy
2. Mouth sores
3. Headaches
4. Chest pain
5. Abdominal pain
6. Fever
7. Chills
8. Loss of appetite
9. Digestive complaints
10. Rash
11. Joint pain
12. Brain fog
...


Acute Inflammation vs. Chronic Inflammation

Inflammation is divided into acute inflammation and chronic inflammation. Acute inflammation occurs over seconds, minutes, hours, and days, whereas chronic inflammation occurs over longer times.

Acute inflammation is initiated by both immune and parenchymal cells at the site of injury, is coordinated by a range of soluble mediators and is characterized by rapid accumulation of immune cells at the site of injury. Key events in acute inflammation include increased blood flow, increased permeability of the capillaries, and migration of immune cells like neutrophils from blood vessels into interstitial spaces. These processes are associated with the localized production of a host of chemical mediators, such as (1) histamine and serotonin, which increase vascular permeability, (2) chemokines, which guide the migration of cells, (3) complement proteins, which assist antimicrobial activity, and (4) cytokines like TNF-alpha, IL-1, and IL-8, which regulate inflammation response.

Although inflammation is an essential component of immunosurveillance and host defense, a chronic low-grade inflammatory state can be harmful. Scientists have studied the effects of inflammation in the pathogenesis of many chronic diseases for several decades. It's now clear that chronic inflammation is detrimental to your health that it may contribute to the development of many disorders such as cardiometabolic, gut and cognitive disorders as well as cancer. Chronic inflammation is also associated with human aging.


Inflammation vs. Infection

Inflammation is not a synonym for infection, though infection can be a cause of inflammation. Infection is the presence of a reproducing pathogen such as viruses, bacteria, and fungi in the body. Inflammation is a response by the body to infection or other types of disturbance. Most infections cause inflammation, but not all. For instance, many viral infections can happen without inflammation. Therefore, inflammation and infection are entirely different things.


Anti-inflammatory therapy

Anti-inflammatory therapy that reduces inflammation is widely used in the clinic. The global anti-inflammatory therapeutics market is expected to garner $106.1 billion by 2020. Anti-inflammatory drugs can be divided into several classes:

1. Nonsteroidal anti-inflammatory drugs (NSAIDs)
2. Immune selective anti-inflammatory derivatives (ImSAIDS)
3. Selective glucocorticoid receptor agonists (SEGRAs)
4. Resolvins and protectins
5. Anti-inflammatory biologics
6. Natural anti-inflammatory agents[4]

These drugs help reduce inflammation, pain, and swelling, and are useful for the treatmetn of arthritis, respiratory diseases, multiple sclerosis, psoriasis, inflammatory bowel disease, and other inflammatory diseases.

In addition to drug therapies, there are other types of treatment to control inflammation. For instance, applying ice or cool water to a tissue injury has an anti-inflammatory effect, and exercise proves to improve the function of skeletal muscle, which in turn reduces the risk of developing inflammatory diseases.



Reference:
[1] Anke Di et al, The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation, Immunity (2018).
[2] H Joe Wang et al, Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development, World journal of gastroenterology (2010).
[3] Tauseef Ali et al, Sleep, immunity and inflammation in gastrointestinal disorders, World journal of gastroenterology (2013).
[4] Ashwani Kumar Dhingra et al, An update on Anti-inflammatory Compounds: A Review, Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (2015).
 
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