Investigating the Early Stages of Inflammation in Arthritis

Researchers here examine the biochemistry and behavior of immune cells in the early stages of arthritis, a condition that is strongly associated with age-related increases in chronic inflammation. Inflammation in turn is associated with growing dysfunction of the immune system with age, a progressive failure that occurs for a variety of reasons, including the presence of metabolically active excess visceral fat tissue that is so common this age of cheap calories; a reduced supply of new immune cells due to declining stem cell activity and involution of the thymus; and dominance of the immune cell population by cells devoted to persistent pathogens such as cytomegalovirus, which cannot effectively assist in responding to new threats. Reducing inflammation should be helpful for arthritis patients, and some of the more common forms of stem cell therapy that achieve this outcome so far appear to be more effective than other options for many of those who undergo the treatments. For much the same reasons, senolytic therapies that target senescent cells for destruction will most likely first enter human trials as arthritis treatments, as senescent cells are another prominent cause of inflammation.

Using a novel approach for imaging the movement of immune cells in living animals, researchers have identified what appear to be the initial steps leading to joint inflammation in a model of inflammatory arthritis. "Inflammatory arthritis is caused when immune cells are recruited from the blood into the joint in a highly regulated process controlled by chemoattractants and adhesion receptors. But when the disease has become symptomatic, it is difficult to determine the initial steps that set off the recruitment of immune cells into the joint and the specific roles of the different chemoattractants. Our study was designed to more fully understand this process. The control of immune cell entry into the joint represents a major point at which new therapies could be developed to reduce the symptoms of inflammatory arthritis."

Inflammatory arthritis includes a number of autoimmune diseases of the joints - including rheumatoid arthritis and lupus - and in many cases is caused by a type of inflammation called type III hypersensitivity. That reaction results when a localized accumulation of immune complexes - antibodies bound to their antigens - is deposited in tissue and sets off an inflammatory response involving the infiltration and activation of immune cells, initially the neutrophil. Current thinking regarding type III hypersensitivity is that immune cells within tissues sense the presence of these immune complexes (ICs) through specific receptor molecules and release inflammatory factors called cytokines that activate the endothelial cells lining adjacent blood vessels to promote the recruitment of neutrophils.

To better determine the role of specific chemoattractants in type III hypersensitivity, researchers used multiphoton intravital microscopy to follow in real time the development of IC-induced arthritis in a mouse model of rheumatoid arthritis. Their experiments revealed that the presence of ICs within the joint space induces the generation of complement C5a, a component of the innate immune system, which is then displayed on the inner walls of adjacent blood vessels. C5a directly initiates the adherence of neutrophils to the vessel walls through interaction with the C5a receptor on neutrophils, which then pass into the joint space and set off inflammation. Once the inflammatory process has been initiated, neutrophils within the joint space release interleukin-1, which induces cells lining the joint space to produce chemoattractants called chemokines that further facilitate the movement of neutrophils into the joint space. Neutrophils within the joint also directly produce chemokines that amplify the cells' recruitment to and survival within the joint space.

Link: https://www.eurekalert.org/pub_releases/2017-01/mgh-tmo011817.php

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