Q: What is chronic inflammation and why does it occur? 

Krishna: Inflammation is part of the body's defense mechanism. It is the process by which the immune system recognizes and removes harmful and foreign stimuli and begins the healing process. Inflammation can be either acute or chronic.

Tissue damage due to trauma, microbial invasion, or noxious compounds can induce acute inflammation. It starts rapidly, becomes severe in a short time and symptoms may last for a few days for example cellulitis or acute pneumonia.

Subacute inflammation is the period between acute and chronic inflammation and may last 2 to 6 weeks.

Chronic inflammation is also referred to as slow, long-term inflammation lasting for prolonged periods of several months to years.

Chronic inflammation can result from the following:

1. Failure of eliminating the agent causing an acute inflammation such as infectious organisms including Mycobacterium tuberculosis, protozoa, fungi, and other parasites that can resist host defenses and remain in the tissue for an extended period.
2. Exposure to a low level of a particular irritant or foreign material that cannot be eliminated by enzymatic breakdown or phagocytosis in the body including substances or industrial chemicals that can be inhaled over a long period, for example, silica dust.
3. An autoimmune disorder in which the immune system recognizes the normal component of the body as a foreign antigen, and attacks healthy tissue giving rise to diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE).
4. A defect in the cells responsible for mediating inflammation leading to persistent or recurrent inflammation, such as auto-inflammatory disorders (Familial Mediterranean Fever).
5. Recurrent episodes of acute inflammation. However, in some cases, chronic inflammation is an independent response and not a sequel to acute inflammation for example diseases such as tuberculosis and rheumatoid arthritis.
6. Inflammatory and biochemical inducers are causing oxidative stress and mitochondrial dysfunction such as increased production of free radical molecules, advanced glycation end products (AGEs), uric acid (urate) crystals, oxidized lipoproteins, homocysteine, and others.

Chronic inflammatory diseases are the most significant cause of death in the world. The World Health Organization (WHO) ranks chronic diseases as the greatest threat to human health.

Worldwide, 3 of 5 people die due to chronic inflammatory diseases like stroke, chronic respiratory diseases, heart disorders, cancer, obesity, and diabetes. The prevalence of some specific chronic inflammation-mediated diseases are as follows:

• Diabetes: 537 million adults (1 in 10) were living with diabetes in 2021. This number is expected rise to 643 million by 2030 and 783 million by 2045.
• Cardiovascular diseases: Cardiovascular diseases (CVDs) accounts for 1 out of every three deaths.  Globally, CVD accounts for 31% of all deaths, and coronary heart disease (CHD) accounts for most deaths due to CVD, followed by stroke and heart failure.
• Arthritis and Joint Diseases: These affect approximately 350 million people worldwide. This number is expected to increse by 2020. 
• Allergies: These rank among the sixth leading cause of chronic human diseases .
• Chronic Obstructive Pulmonary Disease (COPD): Chronic obstructive pulmonary disease (COPD) is a pathology with high morbidity and mortality. Approximately 300 million people have COPD globally , with a prevalence of approximately 12.2%.

Most of the features of acute inflammation continue as the inflammation becomes chronic, including the expansion of blood vessels (vasodilation), increase in blood flow, capillary permeability and migration of neutrophils into the infected tissue through the capillary wall (diapedesis). However, the composition of the white blood cells changes soon and the macrophages and lymphocytes begin to replace short-lived neutrophils. Thus the hallmarks of chronic inflammation are the infiltration of the primary inflammatory cells such as macrophages, lymphocytes, and plasma cells in the tissue site, producing inflammatory cytokines, growth factors, enzymes and hence contributing to the progression of tissue damage and secondary repair including fibrosis and granuloma formation, etc.

Risk Factors Associated with Chronic Inflammation

Several risk factors promote a low-level inflammatory response. These include:

• Age: Increasing age is positively correlated with elevated levels of several inflammatory molecules. The age-associated increase in inflammatory molecules may be due to mitochondrial dysfunction or free radical accumulation over time and other age-related factors like an increase in visceral body fat.
• Obesity: Many studies have reported that fat tissue is an endocrine organ, secreting multiple adipokines and other inflammatory mediators. Some reports show that the body mass index of an individual is proportional to the amount of pro-inflammatory cytokines secreted. Metabolic syndrome typifies this well.
• Diet: Diet rich in saturated fat, trans-fats, or refined sugar is associated with higher production of pro-inflammatory molecules, especially in individuals with diabetes or overweight individuals.
• Smoking: Cigarette smoking is associated with lowering the production of anti-inflammatory molecules and inducing inflammation.
• Low Sex Hormones: Studies show that sex hormones like testosterone and estrogen can suppress the production and secretion of several pro-inflammatory markers and it has been observed that maintaining sex hormone levels reduces the risk of several inflammatory diseases.
• Stress and Sleep Disorders: Both physical and emotional stress is associated with inflammatory cytokine release. Stress can also cause sleep disorders. Since individuals with irregular sleep schedules are more likely to have chronic inflammation than consistent sleepers, sleep disorders are also considered as one of the independent risk factors for chronic inflammation.

Symptoms of Chronic Inflammation

Some of the common signs and symptoms that develop during chronic inflammation are listed below.

• Body pain, arthralgia, myalgia
• Chronic fatigue and insomnia
• Depression, anxiety and mood disorders
• Gastrointestinal complications like constipation, diarrhea, and acid reflux
• Weight gain or weight loss
• Frequent infections

Many dietary and lifestyle changes may be helpful in removing inflammation triggers and reducing chronic inflammation as listed below. The most effective is weight loss. For example, in patients with psoriatic arthritis which is chronic inflammatory arthritis, weight loss alone has been shown to be independently associated with clinically significant improvement in disease activity and inflammation.

• Low-glycemic diet: Diet with a high glycemic index is related to high risk of stroke, coronary heart disease, and type 2 diabetes mellitus. It is beneficial to limit the consumption of inflammation-promoting foods like sodas, refined carbohydrates, fructose corn syrup in a diet.
• Reduce intake of total, saturated fat and trans fats: Some dietary saturated and synthetic trans-fats aggravate inflammation, while omega-3 polyunsaturated fats appear to be anti-inflammatory. Processed and packaged foods that contain trans fats such as processed seed and vegetable oils, baked goods (like soybean and corn oil) should be reduced from the diet.
• Fruits and vegetables: Blueberries, apples, Brussels sprouts, cabbage, broccoli, and cauliflower, that are high in natural antioxidants and polyphenols and other anti-inflammatory compounds, may protect against inflammation. Cherries and cherry juice consumption has been shown to be uricosuric and inhibitory for IL-1 in patients with gout.
• Fiber: High intake of dietary soluble and insoluble fiber is associated with lowering levels of IL-6 and TNF-alpha. 
• Nuts: such as almonds are associated with lowering the risk of cardiovascular disease and diabetes.
• Green and black tea polyphenols: Tea polyphenols are associated with a reduction in CRP in human clinical studies. 
• Curcumin: a constituent of turmeric has been shown to be associated with significant improvement in several inflammatory diseases in animal models.
• Fish Oil: The richest source of the omega-3 fatty acids. Higher intake of omega-3 fatty acids is associated with lowering levels of TNF-alpha, CRP, and IL-6.
• Mung bean: Rich in flavonoids (particularly vitexin and isovitexin). It is a traditional food and herbal medicine known for its anti-inflammatory effects.
• Micronutrients: Magnesium, vitamin D, vitamin E, zinc and selenium). Magnesium is listed as one of the most anti-inflammatory dietary factors, and its intake is associated with the lowering of hsCRP, IL-6, and TNF-alpha activity. Vitamin D exerts its anti-inflammatory activity by suppressing inflammatory mediators such as prostaglandins and nuclear factor kappa-light-chain-enhancer of activated B cells. Vitamin E, zinc, and selenium act as antioxidants in the body.
• Sesame Lignans: Sesame oil consumption reduces the synthesis of prostaglandin, leukotrienes, and thromboxanes and is known for its potential hypotensive activity.

Physical Exercise 

In human clinical trials, it is shown that energy expenditure through exercise lowers multiple pro-inflammatory molecules and cytokines independently of weight loss.

Conventional Drugs that Combat Chronic Inflammation

Metformin is commonly used in the treatment of type II diabetic patients with dyslipidemia and low-grade inflammation. The anti-inflammatory activity of metformin is evident by reductions in circulating TNF-alpha, IL-1beta, CRP, and fibrinogen in these patients.

Statins are anti-inflammatory as they reduce multiple circulating and cellular biomediators of inflammation. This pleiotropic effect appears to contribute in part to the reduction in cardiovascular events.

Non-steroidal anti-inflammatory drugs (NSAIDs) like naproxen, ibuprofen, and aspirin acts by inhibiting an enzyme cyclooxygenase (COX) that contributes to inflammation and are mostly used to alleviate the pain caused by inflammation in patients with arthritis.

Corticosteroids also prevent several mechanisms involved in inflammation. Glucocorticoids are prescribed for several inflammatory conditions including inflammatory arthritis, systemic lupus, sarcoidosis, and asthma.

Herbal supplements like ginger, turmeric, cannabis, hyssop, and Harpagophytum procumbens are shown to have anti-inflammatory properties however one should always consult with a doctor before their use and caution should be taken for using some herbs like hyssop and cannabis.

Although chronic inflammation progresses silently, it is the cause of most chronic diseases and presents a major threat to the health and longevity of individuals. Inflammation is considered a major contributor to several diseases.

• Cardiovascular diseases: Many clinical studies have shown strong and consistent relationships between markers of inflammation such as hsCRP and cardiovascular disease prediction. Furthermore, Atherosclerosis is a pro-inflammatory state with all the features of chronic low-grade inflammation and leads to increase cardiovascular events such as myocardial infarction, stroke, among others.
• Cancer: Chronic low-level inflammation also appears to participate in many types of cancer such as kidney, prostate, ovarian, hepatocellular, pancreatic, colorectal, lung, and mesothelioma.
• Diabetes: Immune cells like macrophages infiltrate pancreatic tissues releasing pro-inflammatory molecules in diabetic individuals. Both circulating and cellular biomarkers underscore that diabetes is a chronic inflammatory disease. Chronic complications linked to diabetes include both microvascular and macrovascular complications. Diabetes not only increases the risk of macrovascular complications like strokes and heart attacks but also microvascular complications like diabetic retinopathy, neuropathy, and nephropathy.
• Rheumatoid arthritis: In a genetically susceptible host, chronic inflammation induced by several environmental factors such as smoking and infections lead to a systemic autoimmune response that causes a local inflammatory response in joints, infiltration of immune cells and release of cytokines. Persistence of chronic inflammation in the synovium in inadequately treated RA has been associated with worse prognosis and radiographic progression of the disease. 
• Allergic asthma: A complex, chronic inflammatory disorder associated with inappropriate immune response and inflammation in conducting airways involving a decline in airway function and tissue remodeling.
• Chronic obstructive pulmonary disease (COPD): An obstructive lung disease, develops as a chronic inflammatory response to inspired irritants and characterized by long-term breathing problems.
• Alzheimer's disease: In older adults, chronic low-level inflammation is linked to cognitive decline and dementia.
• Chronic kidney disease (CKD): Low-grade inflammation is a common feature of chronic kidney disease. It can lead to the retention of several pro-inflammatory molecules in the blood and contributes to the progression of CKD and mortality. Amyloidosis can be a result of underlying chronic inflammation that can lead to severe renal complications.
• Inflammatory Bowel Disease (IBD) is a group of chronic inflammatory disorders of the digestive tract. It can develop as ulcerative colitis causing long-lasting inflammation and ulcers in the lining of large intestine and rectum or Crohn's disease characterized by inflammation of the lining of digestive tract dispersing into affected tissues such as mouth, esophagus, stomach and the anus.  

New information:

Faulty DNA disposal system found to cause inflammation

Cells in the human body contain power-generating mitochondria, each with their own mtDNA—a unique set of genetic instructions entirely separate from the cell's nuclear DNA that mitochondria use to create life-giving energy. When mtDNA remains where it belongs (inside of mitochondria), it sustains both mitochondrial and cellular health—but when it goes where it doesn't belong, it can initiate an immune response that promotes inflammation.

Scientists have discovered a novel mechanism used to remove improperly functioning mtDNA from inside to outside the mitochondria. When this happens, the mtDNA gets flagged as foreign DNA and activates a cellular pathway normally used to promote inflammation to rid the cell of pathogens, like viruses.

The findings, published in Nature Cell Biology, offer many new targets for therapeutics to disrupt the inflammatory pathway and therefore mitigate inflammation during aging and diseases, like lupus or rheumatoid arthritis.

Scientists  knew that mtDNA was escaping mitochondria, but how was still unclear. Using imaging and cell biology approaches, they are able to trace the steps of the pathway for moving mtDNA out of the mitochondria, which they can now try to target with therapeutic interventions to hopefully prevent the resulting inflammation.

One of the ways our cells respond to damage and infection is with what's known as the innate immune system.  While the innate immune response is the first line of defense against viruses, it can also respond to molecules the body makes that simply resemble pathogens—including misplaced mtDNA. This response can lead to chronic inflammation and contribute to human diseases and aging.

Scientists have been working to uncover how mtDNA leaves mitochondria and triggers the innate immune response, but the previously characterized pathways did not apply to the unique mtDNA stress conditions the Salk team was investigating. So, they turned to sophisticated imaging techniques to gather clues about where and when things were going awry in those mitochondria.

 They had a huge breakthrough when the researchers saw that mtDNA was inside of a mysterious membrane structure once it left mitochondria—after assembling all of the puzzle pieces, they realized that structure was an endosome.

That discovery eventually led them to the realization that the mtDNA was being disposed of and, in the process, some of it was leaking out. They  discovered a process beginning with a malfunction in mtDNA replication that caused mtDNA-containing protein masses called nucleoids to pile up inside of mitochondria. Noticing this malfunction, the cell then begins to remove the replication-halting nucleoids by transporting them to endosomes, a collection of organelles that sort and send cellular material for permanent removal.

The endosome gets overloaded with these nucleoids, springs a leak, and mtDNA is suddenly loose in the cell. The cell flags that mtDNA as foreign DNA—the same way it flags a virus's DNA—and initiates the DNA-sensing cGAS-STING pathway to cause inflammation.

Mitochondrial DNA replication stress enacts an endosomal pathway of nucleoid disposal prone to innate immune system activation, Nature Cell Biology (2024). DOI: 10.1038/s41556-023-01343-1. www.nature.com/articles/s41556-023-01343-1