1- What Are cytokines?

Cytokines are small proteins that are produced by white blood cells, such as lymphocytes T and lymphocytes B, and endothelial cells, mast cells, fibroblasts, and mesenchymal cells.

In the nervous system, cytokines are produced by microglia, astrocytes, endothelial cells, and macrophages [1].

• Lymphocytes T

Lymphocytes T are immune cells involved in the killing of viruses and cancer cells.

• Lymphocytes B

Lymphocytes B are immune cells that produce antibodies against viruses, bacteria, and cancer cells. Anomalies in the recognition of the body’s own antigens lead to autoimmune diseases.

• Endothelial Cells

Endothelial cells are the building block of vessels.

• Mesenchymal Cells

Mesenchymal Cells are cells that generate connective tissues.

• Fibroblasts

Fibroblasts are cells found in connective tissues where they produce collagen and are also involved in wound healing.

• Mast Cells

Mast cells are found in connective tissues where they produce histamine (neurotransmitter) and heparin (anticoagulant).

• Macrophages

Macrophages are a type of white cells that are responsible for engulfing and digesting viruses, microbes, cancer cells, debris of cells, and foreign substances.

• Microglia

Microglia are non-neuronal cells that are specifically found in the brain and the spinal cord where they play an essential role in the immune response.

• Astrocytes

Astrocytes are also non-neuronal cells responsible for providing nutrients to the nervous system and support the activity of the nervous system endothelial cells in forming the blood-brain barrier.

2- What Are Chemokines?

Chemokines are also cytokines that control the movement of lymphocytes in response to inflammation, infection, or cancer.

3- What Are Secondary Messengers?

When a ligand such as a growth factor, binds to a receptor on the surface of cells in the body there is a transmission of information within the cells by small molecules and ions that promote the expression of proteins necessary for the function of the cell.

4- What Are Reactive Oxygen Species (ROS)?

Reactive oxygen species (ROS) are produced by the metabolism of oxygen (O2) in the body’s cells. An excess of ROS (e.g., free radicals) can damage the DNA of the cells causing their death or mutations that can lead to cancer.

5- What Causes Neuroinflammation?

• Traumatic Brain Injury

A traumatic brain injury can be mechanical such as a blow to the brain or spinal cord leading to tissue damage, or pathological due to tissue damage caused by excitotoxicity (excessive excitation of neurotransmitters), ischemic injury, or alterations in mitochondria function [2].

• Spinal Cord Injury

A spinal injury is due to an acute or localized (focal) trauma, a reduced blood supply (ischemia), or excitotoxicity.

• Infection

The most known infection of the central nervous system (CNS) is due to Mycobacterium tuberculosis (tuberculosis), but there are other infections such as Plasmodium falciparum (malaria), Rickettsia conorii (Boutonneuse fever), Trypanosoma cruzi (Chagas disease) [3].

These infections cause inflammation by altering the function of the CNS vessels.

• Autoimmunity

Autoimmunity is due to the production of antibodies by lymphocytes B against antigens that are expressed by normal cells, including cells of the brain and spinal cord.

These antibodies are known as autoantibodies and attack the body’s cells and tissues causing their damage and inflammation.

• Toxic Metabolites

Alterations in CNS metabolites (Neurometabolites) such as N-acethylaspartate (NAA), creatine, and glutamine can cause injuries or death of neurons in the central nervous system leading to inflammation.

• Aging

Although the mechanisms are not known, there is an increase in proinflammatory cytokines and a decrease in anti-inflammatory cytokines in the aged central nervous system.

6- What Are the Symptoms of Neuroinflammation?

The symptoms of neuroinflammation depend on the injured part of the central nervous and the type of injury; however, some of the common symptoms are pain, depression, and fatigue.

7- What Mechanisms Mediate Inflammation in the Brain?

The immune response and inflammation in the brain and spinal cord are mainly mediated by microglia and astrocytes but also endothelial cells, and macrophages.

The brain and spinal cord are closed environments due to the presence of the blood-brain barrier (BBB), therefore, not all the cells of the immune system can enter [4].

Following the damage of the brain or spinal cord, microglia are activated and secrete cytokines and chemokines that recruit other cell types such as astrocytes, endothelial cells, and macrophages to repair the damage.

However, during the early stage of spinal injury, there is an infiltration of other immune cells, such as neutrophils, and monocytes. Lymphocytes also contribute to inflammation at a later stage of the injury [1].

9- How Does Neuroinflammation Contribute to Neurodegeneration?

Although the mechanisms are not well known, neuroinflammation has been implicated in the pathogenesis of dementia through its role in cerebral small vessel disease (SVD)-vascular dementia [5].

Neuroinflammation contributes to multiple sclerosis through the disruption of the blood-brain barrier resulting in the recruitment of immune cells and the secretion of proinflammatory factors and antibodies against the myelin sheath.

It was suggested that neuroinflammation also contributes to Alzheimer’s disease through the incapacity of microglia to eliminate amyloid-beta plaques [6].

10- How Is Neuroinflammation Treated?

For multiple sclerosis, a monoclonal antibody (rituximab) has been successfully used to target lymphocytes B responsible for the production of antibodies against the myelin sheet.

However, this treatment has also a potential risk of inducing a rare disease known as progressive multifocal leukoencephalopathy that causes damage to the white matter in multiple parts of the brain [7].

For Alzheimer’s disease and Parkinson’s disease, there are several ongoing clinical trials using inhibitors that regulate the function of microglia and astrocytes which are involved in the pathogenesis of AD and PD [7].

Conclusion

Neuroinflammation is a natural response of the brain and spinal cord to injuries, autoimmunity, infection, toxic metabolites, and aging.

Although its role is to promote the repair of tissues’ damage, proinflammatory cytokines can also result in the recruitment of other types of cells, such as immune cells, fibroblasts, and lymphocytes that can lead to additional and indirect tissue damage resulting in neurodegenerative diseases such as dementia, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.

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What Is Immunosenescence?

Immunosenescence is the process of aging of our immune system which starts to perform less compared to that of a young and healthy individual. Our immune system is divided into two types: innate immunity and acquired immunity also known as adaptive immunity.

1- Immunosenescence of the Innate Immunity

Innate immunity is the first line of defense against bacteria, viruses, fungi, and toxins. This immunity is not specific to the invading pathogen but is rather based on the recognition of conserved features of pathogens, which make it react faster to help destroy invaders [2].

Innate immunity is carried out by natural killer (NK) cells, neutrophils, macrophages, and dendritic cells that are produced in the bone marrow by the hematopoietic stem cells.

While neutrophils, macrophages, and dendritic cells perform their activities through phagocytosis (internalization and destruction of pathogens), Natural killer (NK) cells have a cytotoxic activity through the recognition and release of substances that cause the cell death of the pathogen.

Although the activity of natural killer (NK) cells remains preserved, the phagocytic activities against pathogens of neutrophils, macrophages, and dendritic cells are reduced. However, the number of these cells does not appear to be affected.

2- Immunosenescence of the Adaptive Immunity

Unlike innate immunity, adaptive immunity is a more specialized type of immunity that involves the white blood cells, lymphocytes B, and lymphocytes T [3].

Lymphocytes B are the cells that produce antibodies against pathogens and cancerous cells, while lymphocytes T recognize and destroy pathogens and cancer cells through their cytotoxic activity by inducing cell death.

Lymphocytes B and lymphocytes T are also produced in the bone marrow by the hematopoietic stem cells and become mature in the thymus and spleen and after their activation. With the increase in age, the quantity and quality of lymphocytes B and T immune responses are significantly changed resulting in an impaired immune response.

Older individuals have a diminished capacity to respond to novel antigens (molecules on the outside of pathogens or cancer cells) and vaccines which results in increased susceptibility to infection and the development of age-related diseases such as cancer.

3- Immunosenescence and Inflammation

The function of immune cells is regulated by intercellular (between cells) communications that are mediated by cytokines, a small group of proteins that regulate inflammation. Cytokines are released by different cells in the body, including cells of innate and adaptive immunity.

Some of the cytokines promote inflammation and are known as proinflammatory cytokines, while others have anti-inflammatory activity. During immunosenescence, there is an increase in proinflammatory cytokines due to alterations in the function of immune cells [4][5].

Can We Slowdown Immunosenescence?

Immunosenescence can be slowed down through diet and therapeutic drugs that reduce inflammation.

1- Diet

A diet that is rich in fruits, vegetables, whole grains, legumes, and olive oil (e.g., Mediterranean diet) and that contains fewer sugars and red meat (e.g., cured meat) has been shown to reduce inflammation [6].

Probiotics and prebiotics that have been shown to reduce inflammation can also be provided through diet. For instance, probiotics are found in yogurt, lactobacillus milk, some cheeses such as Gouda, cheddar, cottage cheese, mozzarella, pickles, sauerkraut, kefir, kimchi, tempeh, kombucha, and miso.

Prebiotics are found in carrots, quinoa, radishes, onions, chicory roots, konjac roots, oats, yams, garlic, barley, wheat bran, berries, apples, asparagus, bananas, leeks, chia seeds, flax seeds, cocoa, coconut, jicama root, and dandelion greens.

2- Micronutrients

Micronutrients, such as vitamins and minerals, are critical for the good performance of the immune system. For instance, people with zinc deficiency (e.g., in older individuals) experience increased susceptibility to a variety of pathogens.

Zinc has been shown to have to be crucial for the function of immune cells such as neutrophils, natural killer cells, T lymphocytes, and B lymphocytes [7].

Other micronutrients such as vitamin C also reduce inflammation through its anti-oxidative stress activity.

3- Probiotics and Prebiotics

Probiotics have been shown to prevent inflammation associated with allergies, diabetes type 2 (Diabetes Miletus), autoimmune diseases, rheumatoid arthritis, cancer.

Because they produce lactic acid, the probiotics, Lactobacillus and Bifidobacterium, suppress pathogens’ induction of immunomodulatory molecules that can induce inflammation.

Prebiotics induce the expression of cytokines that promote communication between immune cells leading to improved immune response and protection against infections and other diseases such as cancer and neurodegenerative diseases.

The administration of the prebiotic fructo-oligosaccharides improves antibody response to viral vaccines, upregulates toll-like receptor 2-mediated immune response, and increased phagocytosis, and the levels of NK cells and the anti-inflammatory IL-10.

4- Bioactive Compounds

Resveratrol is a polyphenol found in red wine that has antiaging and anti-diabetic properties and is used as a nutritional supplement. Resveratrol has been shown to increase the levels of the NAD-dependent deacetylase sirtuin-1 (SIRT-1), a protein that is involved in the cellular response to inflammatory, metabolic, and oxidative stressors.

Sulforaphane (SFN) is an isothiocyanate that is present in cruciferous vegetables such as cauliflower, cabbage, kale, garden cress, bok choy, broccoli, and Brussels sprouts. Sulforaphane has been shown to inhibit inflammation by inhibiting the pro-inflammatory factor NFkB and by promoting antioxidation via the induction of NrF2, a master regulator of detoxification, anti-inflammation, and antioxidation processes within the cells.

Conclusion

Immunosenescence is a natural process of aging that results in alterations in the immune system leading to increased susceptibility to infections, reduced response to vaccines, and increased inflammation. However, immunosenescence can be slowed down through appropriate and healthy diets and food supplements that help the function of the immune system.

References

[1] https://www.who.int/news-room/fact-sheets/detail/ageing-and-health

[2] Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K. and Walter, P., 2002. Innate immunity. In Molecular Biology of the Cell. 4th edition. Garland Science.

[3] Bonilla, F.A. and Oettgen, H.C., 2010. Adaptive immunity. Journal of Allergy and Clinical Immunology, 125(2), pp.S33-S40.

[4] Licastro, F., Candore, G., Lio, D., Porcellini, E., Colonna-Romano, G., Franceschi, C. and Caruso, C., 2005. Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immunity & Ageing, 2(1), pp.1-14.

[5] Miquel, J., 2009. An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging. Current pharmaceutical design, 15(26), pp.3003-3026.

[6] Vasto, S., Buscemi, S., Barera, A., Di Carlo, M., Accardi, G. and Caruso, C., 2014. Mediterranean diet and healthy ageing: a Sicilian perspective. Gerontology, 60(6), pp.508-518.

[7] Shankar, A.H. and Prasad, A.S., 1998. Zinc and immune function: the biological basis of altered resistance to infection. The American journal of clinical nutrition, 68(2), pp.447S-463S.

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1. What Are the Stages of Wound Healing?

Homeostasis Phase

This phase involves blood vessels’ vasoconstriction (tightening) and platelet aggregation to stop blood loss at the injured site.  Platelet aggregation, also known as coagulation, relies on a primary homeostasis stage and a secondary homeostasis stage [2].

In the first stage, platelets aggregate to form a plug that prevents bleeding, and in the second. In the second stage, intrinsic and extrinsic coagulation pathways are activated through a series of clotting factors.

Intrinsic coagulation factors are activated by the wound-exposed endothelial collagen and include factors I (fibrinogen), II (Prothrombin), IX (Christmas factor), X (Stuart-Prower factor), XI (Plasma Thromboplastin), and XII (Hageman factor).

Extrinsic factors, also named stable factors are activated by tissue factors released by damaged endothelial cells and include factors I, II, VII, and X.

Inflammatory Response Phase

After coagulation, the vasoconstriction that characterizes the homeostasis phase is replaced by vasodilation (opening) that promotes the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury and their binding to the scaffolding that was constructed by the platelets’ aggregation.

Once on-site, neutrophils initiate the phagocytosis and killing of pathogens to decontaminate the wound, while also promoting cell proliferation and angiogenesis.

Besides their direct role in the phagocytosis and killing of pathogens, Monocytes which become macrophages, also remove apoptotic cells and support cell proliferation and tissue restoration following injury.

Endothelial cells are the building blocks for vessels, and during wound healing, these cells generate new vessels (angiogenesis) to satisfy the metabolic demands of the highly proliferative healing tissue. 

 Proliferation Phase

In this phase, keratinocytes, fibroblasts, macrophages, and endothelial cells are extensively activated to contribute to the closure, matrix deposition, and angiogenesis at the wound site [3]. 

keratinocytes in the surroundings of the wound migrate across the wound to reform the epidermal layer through a process known as epithelialization [4]. During this process, hair follicle stem cells are also activated to generate hair on the newly healed skin tissue.

While the epithelialization is ongoing, fibroblasts proceed to the breakdown of the fibrin clot and the deposition of a new extracellular matrix (ECM) and collagen to build structures that support the effective wound-healing effort of the other cells [5].

Although macrophages play a role during the inflammatory response phase, their functions during the proliferation phase are also critical in guiding the proper formation of vessels and in supporting fibroblasts in the breakdown of fibrin [6].

Remodeling Phase

This process is associated with the deposition of collagen by fibroblasts to replace the initial fibrin clot. Although collagen deposition contributes to the scarification of the wound, this deposited collagen is different from the one that was initially present in the unwounded tissue and will only confer for up to 80% of pre-wounding strength [7].

Other components that are required for the remodeling phase include myofibroblasts that secrete alpha-smooth muscle actin (α-SMA), necessary for the generation of strong contractile forces and focal adhesions, and elastin that provide skin elasticity to the healed wound.

2. What Slowdown Wound Healing?

Diabetes and Wound Healing

During the inflammatory response phase, vasodilation of the blood vessels is necessary for the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury.

However, due to the high levels of glucose in the blood of diabetics, the arteries are thickened, resulting in vasoconstriction of the blood vessels which slows down wound healing. 

Another pathological process that can slow down wound healing in diabetics is associated with nerve damage that is caused by high levels of glucose which leads to poor blood circulation.

Malnutrition and wound healing

Micronutrients (minerals and vitamins) and macronutrients (Proteins, lipids, and carbohydrates) are required for effective wound healing. For instance, proteins are necessary for the production of enzymes, collagen, and connective tissue during the remodeling phase of wound healing.  

Neutrophils, monocytes, fibroblasts, endothelial cells, and myofibroblasts require glucose to generate energy for their activity during wound healing. Lipids are necessary for the generation of new cellular membranes.

In addition, vitamin A enhances the early inflammatory response phase and promotes epithelial cell differentiation, and vitamin C promotes the migration of neutrophils and is necessary for the production of collagen.

Finally, zinc is required for DNA and protein synthesis, and cell division during the proliferation stage of wound healing [8].

Smoking and Wound Healing

Clinically, it is well accepted that cigarette smoking delays wound healing as the toxic constituents of cigarette smoke such as nicotine, carbon monoxide, and hydrogen cyanide can affect nutritional blood flow to the skin, which impairs healing of the injured tissue.

Carbon monoxide is known to reduce oxygen transport and metabolism’ while hydrogen cyanide is also a known inhibitor of enzymatic systems required for cellular oxidative metabolism and oxygen transport [9]. 

3. How to Improve Wound Healing?

The consumption of the following foods can improve wound healing:

• – Drinking plenty of water for hydration (if recommended).
• – Proteins (e.g., in lean meat, beans, lentils, and dairy products).
• –  Carbohydrates (e.g., in whole-grain bread and cereals, potatoes, and rice)
• – Vitamins and minerals: vitamin A (e.g., in the liver, milk, eggs, and leafy greens), vitamin C (e.g., in broccoli, strawberries, tomatoes, and kiwi), and Zinc (e.g., in seafood, beans, lentils, and whole-grain bread).

4. Frequently Asked Questions about What Are the Mechanisms of Wound Healing?

What are the stages of wound healing?

Wound healing typically progresses through three main stages: inflammation, proliferation, and remodeling.

What happens during the inflammation stage of wound healing?

During inflammation, the body’s immune response is activated to clear debris and prevent infection. Blood vessels constrict to reduce bleeding, followed by dilation to increase blood flow, bringing white blood cells to the wound site.

What occurs during the proliferation stage of wound healing?

In the proliferation stage, new tissue is formed to repair the wound. This involves the proliferation of fibroblasts, which produce collagen, as well as the formation of new blood vessels (angiogenesis) to supply nutrients to the healing tissue.

What is the role of fibroblasts in wound healing?

Fibroblasts are key cells involved in wound healing. They produce collagen, which provides structural support to the healing tissue, and they also help to contract the wound, reducing its size.

What is angiogenesis and why is it important in wound healing?

Angiogenesis is the formation of new blood vessels. It is crucial in wound healing because it ensures that the healing tissue receives an adequate blood supply, delivering oxygen and nutrients necessary for repair.

How does the remodeling stage contribute to wound healing?

During the remodeling stage, the newly formed tissue undergoes maturation and remodeling. Collagen fibers reorganize to increase tissue strength, and excess scar tissue may be broken down.

This stage can last for months to years, gradually improving the strength and appearance of the healed wound.

What factors can affect the wound healing process?

Various factors, including age, underlying health conditions (such as diabetes or immunodeficiency), nutritional status, medications (such as steroids or chemotherapy), and the presence of infection, can influence the speed and effectiveness of wound healing.

How can I promote optimal wound healing?

To support wound healing, it’s essential to maintain good overall health, including adequate nutrition, hydration, and hygiene.

Following medical advice regarding wound care, avoiding smoking, managing chronic conditions, and protecting the wound from further injury can also facilitate healing.

Conclusion

Wound healing involves the participation of different cells, cytokines, mediators, and the vascular system to repair the damaged tissue. However, to fuel this amazing repair machinery, an appropriate diet that provides proteins, lipids, carbohydrates, vitamins, and minerals is necessary for effective wound healing.

References

[1] Wallace, H.A., Basehore, B.M. and Zito, P.M., 2017. Wound healing phases.

[2] Chaudhry, R., Usama, S.M. and Babiker, H.M., 2018. Physiology, coagulation pathways.

[3] Wilkinson, H.N. and Hardman, M.J., 2020. Wound healing: Cellular mechanisms and pathological outcomes. Open biology, 10(9), p.200223.

[4] Santoro, M.M. and Gaudino, G., 2005. Cellular and molecular facets of keratinocyte reepithelization during wound healing. Experimental cell research, 304(1), pp.274-286.

[5] Driskell, R.R., Lichtenberger, B.M., Hoste, E., Kretzschmar, K., Simons, B.D., Charalambous, M., Ferron, S.R., Herault, Y., Pavlovic, G., Ferguson-Smith, A.C. and Watt, F.M., 2013. Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature, 504(7479), pp.277-281.

[6] Willenborg, S., Lucas, T., Van Loo, G., Knipper, J.A., Krieg, T., Haase, I., Brachvogel, B., Hammerschmidt, M., Nagy, A., Ferrara, N. and Pasparakis, M., 2012. CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair. Blood, The Journal of the American Society of Hematology, 120(3), pp.613-625.

[7] Young, A. and McNaught, C.E., 2011. The physiology of wound healing. Surgery (Oxford), 29(10), pp.475-479.

[8] MacKay, D.J. and Miller, A.L., 2003. Nutritional support for wound healing. Alternative medicine review, 8(4).

[9] Silverstein, P., 1992. Smoking and wound healing. The American journal of medicine, 93(1), pp.S22-S24.

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