Regulation of Inflammation

Rheumatoid Arthritis, Psoriasis, and Other Inflammatory Diseases

Activation of immune cells induces the expression of inflammatory cytokines, chemokines, enzymes, and adhesion molecules that play a critical role in the natural response to both infection and tissue injury. Under normal circumstances, this process of inflammation is tightly regulated and resolves once the infection is cleared or the tissue is repaired. However, if unchecked, chronic inflammation can lead to a host of debilitating diseases such as rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.

Scientists at MMRI are exploring the physiological mechanisms that cells of the immune system utilize to terminate inflammation and limit tissue destruction. Understanding and leveraging these natural mechanisms may foster the development of therapeutics that prevent tissue damage caused by acute and chronic inflammation.

MMRI investigators have discovered that modulation of specific cell-surface protein receptors effectively prevents sustained inflammation and subsequent tissue damage. One such receptor is the adenosine A2A receptor (A2AR). Adenosine is a key natural ligand that binds the A2AR and is found widely in nature and plays an important role in many biochemical processes. Adenosine is a component of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) involved in energy transfer, and plays a role in signal transduction as cyclic adenosine monophosphate (cAMP).

During inflammation and targeted immune responses, inflammatory cells are metabolically very active and produce adenosine as a byproduct of this metabolic activity. The adenosine produced during an immune response acts as a negative regulator of that immune response by binding A2AR on key immune cells and inhibiting further inflammation and immune activation.

MMRI investigators have discovered a series of compounds that modulate the activity of A2AR. One class of compounds MMRI is exploring are known as allosteric modulators, that bind A2AR but not at the active site, and do not appear to alter the simultaneous binding of adenosine to the same A2AR receptor. These allosteric modulators can effect either positive or negative modulation, increasing or decreasing respectively, the activity of the receptor when it binds its natural ligand, adenosine.

MMRI has discovered a family of compounds that act as positive allosteric modulators of A2AR; once such compound is AEA061. We are exploring the activity of this and similar compounds in a variety of inflammatory models and characterizing their effectiveness in these models. As a positive allosteric modulator, AEA061 binds A2AR at a site different than the active site. When adenosine binds the same receptor at the active site, the modulator has the effect of increasing the activity of the receptor. So if adenosine acts to inhibit the local immune response when binding A2AR, then AEA061 potentiates this response, providing increased inhibition. One working hypothesis is that augmenting the natural, endogenous adenosine feedback response with a positive allosteric modulator, might allow the immune response to re-set back into a healthy homeostatic range. We are proposing to call this type of intervention an immune setpoint regulator.

Scientists at MMRI have published a series of scientific papers describing AEA061 and it’s activity in inflammatory models of general inflammation, chronic arthritis, and psoriasis. Links to these papers are available on the publications page.

MMRI is also exploring negative allosteric modulators of A2AR. Naturally, these would have the opposite effect of a positive allosteric modulator. In the case of inflammation and immune response, a negative allosteric modulator could potentially increase or potentiate the immune response. These compounds may have activity in cancer, where an increased immune response might be beneficial. Other scenarios include increasing an immune response to viral infections and other infectious diseases. Early in vitro data shows that negative allosteric modulation of A2AR is possible and biologically plausible.

To learn more about arthritis and inflammatory diseases of the skin:
National Institute of Arthritis, Musculoskeletal and Skin Diseases – National Institutes of Health