Reducing Systemic Inflammation via TLR4 Knockout

TLR4 is one of a number of cell surface receptors that mediate innate immune cell reactions to molecules indicative of damage in the body. Some fraction of the chronic inflammation of aging is caused by increases in damage-associated molecular patterns that trigger receptors of this nature, and consequent maladaptive reactions on the part of the innate immune system. Does it help to block this trigger? In mice, yes. Knockout of TLR4 leads to mice that have improved insulin metabolism and cardiovascular health in old age. TLR4 might be a good example of antagonistic pleiotropy. Natural selection has produced mice equipped with a more aggressive innate immune response, helpful in youth, at the cost of a more rapid deterioration in later life.

A growing amount of evidence suggests that inflammation plays a critical role in the physiological aging process. Many studies have shown that the activated chronic inflammatory response is involved in aging-related diseases. Aging-related inflammation is characterized by increased levels of IL-6, IL-1β, TNF-α, and type I interferon. This chronic activation of the innate immune system in the absence of infection during the aging process is called inflammaging. The activated innate immune system in aging causes insulin resistance and oxidative processes, making the cardiovascular system more vulnerable to stress, thereby increasing the risk of cardiovascular diseases. Moreover, some studies have shown that inhibiting inflammation could reduce the occurrence of cardiovascular diseases in aging, suggesting the important role of inflammation in aging-induced cardiovascular injury.

The mechanism responsible for inflammaging is still far from clear. Metabolic disorders, mitochondrial dysfunction, DNA damage, and autophagy deficiency are all involved in inflammaging. The damaged DNA or self-derived molecules released from damaged cells are called damage-associated pattern molecules (DAMPs). Usually, DAMPs are transferred into lysosomes and then degraded. The accumulation of excessive DAMPs will lead to inflammation. TLR4 is an innate immune receptor that specializes in sensing DAMPs. When sensing DAMPs, TLR4 triggers intracellular signaling pathways which subsequently activate downstream inflammatory responses, leading to the release of inflammatory factors.

The effects of TLR4 on the cardiovascular system of aged mice were investigated in TLR4-/- mice. In wild-type mice, TLR4 expression increased in the hearts and aortas of mice in an age-dependent manner. Loss of TLR4 increased insulin sensitivity in aged mice. Moreover, loss of TLR4 improved cardiac performance and endothelium-dependent vascular relaxation in aged mice. Importantly, the increases in serum inflammatory cytokines and oxidative stress in the heart and aorta were also inhibited by TLR4 deficiency. The reduced inflammatory responses and oxidative stress may be the reason for the protective effects of TLR4 deficiency during aging. Our study indicates that targeting TLR4 is a potential therapeutic strategy for preventing aging-related cardiovascular disease.



CRISPR screen identifies new anti-inflammatory drug target
Date: November 11, 2021
Source: Vanderbilt University Medical Center
Summary: A metabolic enzyme that has been studied in cancer biology and is important for T cell function may offer a new target for anti-inflammatory therapeutics, researchers have discovered. They report that inhibiting or genetically deleting the enzyme, called MTHFD2, reduced disease severity in multiple inflammatory disease models.

Posted by: Jones at November 16th, 2021 1:23 PM


Exercise increases the body's own 'cannabis-like' substance which reduces chronic inflammation
Date: November 17, 2021
Source: University of Nottingham
Summary: Exercise increases the body's own cannabis-like substances, which in turn helps reduce inflammation and could potentially help treat certain conditions such as arthritis, cancer and heart disease.

'A group of scientists, led by Professor Ana Valdes from the School of Medicine at the University, tested 78 people with arthritis. Thirty-eight of them carried out 15 minutes of muscle strengthening exercises every day for six weeks, and 40 did nothing.

At the end of the study, participants who did the exercise intervention had not only reduced their pain, but they also had more microbes in their guts of the kind that produce anti-inflammatory substances, lower levels of cytokines and higher levels of endocannabinoids.
'The increase in endocannabinoids was strongly linked to changes in the gut microbes and anti-inflammatory substances produced by gut microbes called SCFAS. In fact, at least one third of the anti-inflammatory effects of the gut microbiome was due to the increase in endocannabinoids.'
'Doctor Amrita Vijay, a Research Fellow in the School of Medicine and first author of the paper, said: "Our study clearly shows that exercise increases the body's own cannabis-type substances. Which can have a positive impact on many conditions.

"As interest in cannabidiol oil and other supplements increases, it is important to know that simple lifestyle interventions like exercise can modulate endocannabinoids."'

Posted by: Jones at November 19th, 2021 2:28 AM
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