Chronic Inflammation:Causing Mechanisms and Unhealthy Effects

Inflammation, a seemingly subtle condition, actually has profound effects on health. From traditional Chinese medicine concepts like "excessive internal heat" to modern medical analysis of the link between inflammation and chronic diseases. Inflammation can be divided into two types- acute and chronic. However, chronic inflammation, due to its persistence, is often difficult to identify and treat promptly, leading to various health problems. For example, chronic inflammation can contribute to cardiovascular diseases like atherosclerosis by damaging the inner walls of blood vessels; exacerbate symptoms of sleep apnea, affecting sleep quality. Moreover, chronic inflammation is associated with cognitive decline and potentially increasing the risk of Alzheimer's disease. Nowadays, chronic inflammatory diseases have been identified as a major cause of mortality globally, accounting for more than half of all deaths worldwide. The World Health Organization (WHO) considers chronic diseases as the biggest threat to human health.


What is Inflammation?

Inflammation is a biological response, a natural and complex defense mechanism that the body initiates in response to injury, infection, or other stimulations. It is well known that inflammation involves in various physiological and pathological processes within the body by activating the immune system, blood vascular systems, and cells within damaged tissues. Its primary purpose is to clear damaged tissue or pathogens and promote tissue repair, helping the body maintain tissue homeostasis under various harmful conditions. [1]


Inflammation is commonly caused by factors such as microbial infections, allergic reactions, or mechanical injuries. Microbial infections are a common cause, including bacteria, viruses, fungi, and parasites. When they spread in the body, they release toxins and metabolic products, triggering immune responses that damage tissue cells, leading to inflammatory reactions. Allergens also can lead to inflammatory responses. Mechanical injuries mainly include burns, bruises, and frostbite, which can easily lead to wound infections under improper care, thereby inducing inflammatory reactions.



Inflammation Activation Mechanisms


Although the specific process of the inflammatory response depends on the nature of the initial stimulus and its location in the body, all inflammatory responses involve four basic components. [2]

[Diagram 1: Four Stages of Inflammation Activation] [2]


First, the inflammatory response is triggered by inflammatory inducers, which can be bacteria, viruses, or physical trauma, among other initial stimuli. They activate the body's immune defense mechanisms, marking the beginning of the inflammatory process. Second, cellular sensors, such as Toll-like receptors (TLRs) on the surface of immune cells, recognize and bind to these inflammatory inducers, thereby activating intracellular signaling processes, which is a crucial first step in the inflammatory response. Subsequently, when cellular sensors are activated, they trigger various inflammatory pathways including NF-kB, MAPK, and JAK-STAT, among others. The activation of these pathways leads to the release of inflammatory mediators, including cytokines, chemokines, and enzymes, which further amplify the inflammatory response. Finally, inflammatory mediators cause vasodilation and increased vascular permeability, promoting the recruitment of inflammatory cells such as neutrophils, monocytes, and lymphocytes. These cells migrate to the site of inflammation and participate in the clearance of pathogens and damaged organ tissues, such as the vascular endothelium in cardiovascular diseases, gums in periodontitis, or knee joints in arthritis, leading to local manifestations of inflammation such as redness, swelling, heat, pain, and functional impairment.



Common inflammatory signaling pathway[3]


[Diagram 2: Classical Inflammatory Signaling Pathways] [4]


NF-κB Pathway: NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a crucial transcription factor that plays a central role in the inflammatory response. It identifies extracellular inflammatory signals, activates signaling pathways, leading to the phosphorylation and degradation of IκB proteins, thereby releasing the NF-κB complex and promoting its translocation into the cell nucleus. In the nucleus, the NF-κB complex binds to the promoters of target genes, activating the transcription of inflammatory mediators. These mediators collectively promote the recruitment of inflammatory cells and sustain the inflammatory response.[5]


MAPK Pathway: The MAPK (mitogen-activated protein kinase) family includes various kinases such as ERK1/2, p38 MAPK, and JNK, which can respond to various external stimuli, including changes in osmotic pressure, mitogens, heat shock, and inflammatory cytokines. The activation of the MAPK pathway is a hierarchical phosphorylation process, initiated by MAPKKK, followed by the activation of MAPKK, ultimately triggering the activity of MAPK. These activated MAPKs further phosphorylate various downstream target proteins, including transcription factors involved in inflammation regulation. Through this mechanism, the MAPK pathway enhances the expression of inflammatory cytokines, promotes the synthesis and release of inflammatory mediators, amplifying the inflammatory response, playing a central role in activating and mobilizing immune cells, and serving as an indispensable regulatory mechanism in the inflammatory process. [6]


JAK-STAT Pathway: The JAK-STAT signaling pathway regulates the inflammatory process in response to stimuli such as cytokines, growth factors, and interferons. When these cytokines bind to their respective receptors, they trigger the activation and mutual phosphorylation of receptor-associated JAKs, providing binding sites for STAT proteins. Subsequently, STAT proteins are phosphorylated, forming dimers, which then translocate to the cell nucleus and bind to the promoter regions of inflammation-related genes, activating their transcription. This promotes the activation, proliferation, and differentiation of inflammatory cells, enhances immune responses, and drives the progression of the inflammatory reaction. [7]



Common Signs of Inflammation


Inflammation is a biological phenomenon known for thousands of years, associated with two major injuries of the past - wounds and infections. The Roman physician Cornelius Celsus first defined the clinical symptoms of inflammation as redness, swelling, heat, and pain, with later research adding dysfunction as the fifth sign.


Internally, the manifestations of inflammation typically include the following aspects:

i. Vasodilation and increased vascular permeability: Vasodilation leads to increased blood flow, with red blood cells and white blood cells accumulating in the damaged area, while increased vascular permeability facilitates the entry of immune cells into damaged tissues.

ii. Leukocyte infiltration: Leukocytes are a major component of the immune system, and they gather in damaged tissues, participating in the clearance of pathogens and damaged cells.

iii. Tissue edema: Increased vascular permeability allows fluid and proteins to leak from blood vessels into the tissue, resulting in edema.


Externally, the manifestations of inflammation typically include the following aspects:

i. Redness, swelling,and pain: Redness, swelling, heat sensation, and pain in the affected tissues are typical manifestations of inflammation. This is due to increased blood flow and tissue edema caused by vasodilation and the release of inflammatory mediators, stimulating nerve endings to cause pain.

ii. Increased secretion: The inflammatory site may produce exudates. These exudates contain cell debris, cytokines, and other inflammatory mediators produced during the inflammatory response.

iii. Functional impairment: The function of damaged tissues is usually affected, such as joint inflammation leading to restricted joint movement, or respiratory tract infections causing breathing difficulties.

iv. Systemic symptoms: Severe inflammatory reactions may cause systemic symptoms such as fever, fatigue, and headache.






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4.     The NF-κB Pathway: a Focus on Inflammatory Responses in Spinal Cord Injury.DOI: 10.1007 s12035-023-03411-x

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6.     p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. DOI: 10.1038 nrd1177

7.     JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. DOI: 10.1007 s40265-017-0701-9