Deep Cell: 30-year mystery! Scientists have revealed the pros and cons of stress in causing inflammatory responses.

Most studies have shown that acute stress reduces the host's ability to adapt to inflammation in a variety of diseases, and scientists have been exploring how acute stress reduces the host's adaptability to inflammation.in 1990, it was found that the level of peripheral cytokine IL-6 increased after acute stress (1), but the mechanism by which this inflammatory factor affects the body's function is not very clear.on June 23, 2020, Andrew Wang, Department of immunology, Yale University School of medicine, published an article in the journal Cell, which solved the problem that has puzzled the scientific community for 30 years, and answered the specific mechanism of the effect of the increase of IL-6 level caused by acute stress on the body function.the picture is from literature 2. The advantages and disadvantages of stress-induced inflammatory reaction, researchers through tube restraint model, social isolation model and other acute stress mice blood IL-6 levels increased significantly. The levels of CXCL1, IL-5, IL-6 and GCSF were significantly increased, but IL-6 was the most significant cytokine. Br / > however, the level of IL < 6 times higher in the mice than in the human tissues was found after further stress.IL-6 is produced by a variety of cell types including hematopoietic cells, cardiomyocytes, endothelial cells and adipocytes (3).in order to study the specific source of IL-6 after acute stress, the researchers of hard nucleus screened 16 kinds of tissues, including brain tissues such as midbrain and forebrain, peripheral organs such as lung, liver, heart and kidney; muscle, brown adipose tissue (BAT); white adipose tissue of epididymis; retroperitoneal white adipose tissue. The results showed that only the level of IL-6 in brown adipose tissue of stressed mice was obvious There was a significant increase.after surgical resection of brown adipose tissue, the level of IL-6 in stressed mice did not increase.these results indicate that the increased peripheral IL-6 after stress mainly comes from brown adipose tissue.brown adipose tissue is enriched in the expression of adrenergic receptors, which produce heat with the help of uncoupling protein 1.the researchers directly injected the agonists of adrenergic receptor 1, 2 and 3 into mice respectively. The results showed that only the agonists of adrenergic receptor 3 could promote the increase of IL-6 level in mice. In addition, the level of IL-6 did not increase after giving the antagonist of adrenergic receptor 3 or specifically knocking out the adrenergic receptor 3 on brown adipose tissue before stress This indicates that adrenergic receptor 3 on brown adipose tissue regulates the increase of IL-6 level after stress.fight or flight response (fight or flight response) was first proposed by American psychologist white cannon in 1929. It produces a series of stress behaviors and physiological reactions when facing threats.Although previous studies have shown that IL-6 can be induced as hyperglycemia, hyperglycemia is a typical feature after acute stress.but in this study, the researchers found that hyperglycemia was not responsible for IL-6 production.however, this does not prevent IL-6 from regulating the fight or flight response through hyperglycemia.in the face of a threat to fight or escape, a large amount of energy storage is required, of which glucose is the most critical.mice were still in hyperglycemia level 4 hours after acute stress, and mice treated with IL-6 recombinant protein produced hyperglycemia similar to stress induced hyperglycemia.after inhibition of IL-6 signaling pathway, glucose production in stressed mice decreased.this brings a new question: where does the glucose come from? The liver and kidney are the main glucose producing organs. Through transcriptomics, the researchers found that only the genes of liver induced glucose production changed significantly during acute stress.in addition, only liver glucose was reduced in these stressed mice treated with Anti-IL-6 receptor il-6ra antibody.in order to further confirm that the increase of IL-6 after stress is necessary for the liver to produce high blood glucose, they did not observe the increase of glucose level in several stress models after specifically knocking out the IL-6 in the liver, indicating the control effect of IL-6 on liver glucose synthesis.then does impaired glucose production affect adaptive behavior in acute stress? In the dark box experiment, the researchers found that acute stress mice spent more time in the dark, which was a normal escape behavior; while the IL-6 mice on the specific knockout liver did not show such an increase, which indicated that stress-induced IL-6 regulated liver mediated stress-induced hyperglycemia through il-6ra signal. This positive energy balance for adaptive behavior response is Required.then in pathological state, the increase of IL-6 level will aggravate the inflammatory reaction? The researchers used LPS (lipopolysaccharide) to induce inflammation in mice. Normally, this model does not cause death in mice, but the mortality of mice is significantly increased after acute stress such as tube restraint and social isolation.what is more surprising is that after administration of adrenergic receptor 3 agonists or a single dose of IL-6, the mortality of mice after LPS model was also significantly increased, which indicated that IL-6 was involved.however, the administration of adrenergic receptor-3 antagonist could significantly reduce the high mortality rate caused by tube binding.also showed that stress-induced IL-6 reduced the host's adaptability to the subsequent inflammatory response.pictures from Ref.References: 1. LeMay, L.G., Vander, A.J., and Kluger, M.J. (1990). The effects of psychological stress on plasma interleukin-6 activity in rates. Physical. Behav. 47, 957 – 9612. Qing et al., origin and function of stress-induced IL-6 in murine models, cell (2020), hunter, C.A., and Jones, S.A. (2015). IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 16, 448–457