MIPS researchers find piece in inflammatory disease puzzle

May 2017

Inflammation is part of the body’s natural healing process, but when it gets out of control it can cause disease. Monash Institute of Pharmaceutical Sciences (MIPS) researchers, in collaboration with researchers from the Monash Biomedicine Discovery Institute (BDI) have shed light on a key aspect of this process. Their findings may help guide the development of new treatments of inflammatory diseases such as atherosclerosis, which can lead to heart attack or stroke, and type 2 diabetes.

Published in the journal Science Signaling, the research reveals how certain proteins cause the white blood cells that play a central role in inflammatory responses to behave in different ways. White blood cells are beneficial in helping to eliminate invading microorganisms or repair damaged tissue, but sometimes they prolong the response and damage healthy tissues, leading to disease.Dr Canals

These proteins, called chemokines, are secreted into blood vessels and activate chemokine receptors embedded in the outer membranes of the white blood cells. While it was previously thought that this occurred like an on-off switch, the scientists found that the chemokine receptor can behave more like a ‘dimmer switch’ with one chemokine giving a strong signal and another giving a weaker signal. They found that different responses can be caused by different chemokines activating the same receptor.

This explained for the first time the mechanism by which white blood cells produced varying responses: a strong short-lived response (acute inflammation) or a steady, longer-lived response (chronic inflammation).

“Until now, we did not understand how this was possible,” said co-lead author Associate Professor Martin Stone.

“Our work has identified the specific features of chemokines and receptors that are involved in their inflammatory activity,” Associate Professor Stone said.

“The ultimate goal is to develop anti-inflammatory drugs that target these molecules,” he said.

“By understanding how chemokines engender graded responses at their receptors, we are better placed to understand and develop more specific and efficacious drugs”, said Dr Canals, a Monash Fellow at MIPS.

“This also might give some insight into how the body fine tunes immune responses”, she said

The findings will have wide implications as the proteins involved are essential to all inflammatory diseases.

Associate Professor Stone, who heads a laboratory in the Infection and Immunity Program at the Monash BDI collaborated closely with co-lead author Dr Meritxell Canals who leads a laboratory at Drug Discovery Biology at MIPS. First author was PhD student Mrs Zil E. Huma.

Read the full paper titled Key determinants of selective binding and activation by the monocyte chemoattractant proteins at the chemokine receptor CCR2.