Scientists shed light on a key molecular mechanism of autoimmune and inflammatory diseases

January 17, 2018, VIB (the Flanders Institute for Biotechnology)

An international team of researchers led by prof. Savvas Savvides (VIB-UGent Center for Inflammation Research) has unraveled a crucial aspect of the molecular basis of autoimmune and inflammatory diseases such as psoriasis, rheumatoid arthritis and Crohn's disease. Focusing on the immunomodulatory cytokine IL-23 they discovered that its pro-inflammatory activity, which underlies a wide range of inflammatory diseases, critically depends on structural activation of the cytokine by its receptor, IL-23R. The results of the study are published in the leading journal Immunity.

The prevalence of psoriasis, , inflammatory bowel diseases, and multiple sclerosis, has been rapidly expanding over the last few decades. For instance, an estimated 125 million people worldwide are affected by psoriasis and another 100 million by rheumatoid arthritis, while the presence of inflammatory bowel diseases (Crohn's and ulcerative colitis) in ethnic populations and previously unaffected geographical regions is growing at alarming rates. The cytokine IL-23 – a specific type of immunomodulatory protein – plays a crucial role in these diseases. Consequently, IL-23 has become the focus of against such diseases.

Reversed roles: when receptor activates cytokine

Since the first description of IL-23 about a decade and a half ago, the structural and for the mechanisms underlying the pro-inflammatory activity of IL-23 remained unclear. Prof. Savvides and his team have now shed light on the unique way that IL-23 interacts with at least one of its receptors. In general, cytokines activate receptors. But surprisingly, in the current study, the opposite appeared to be true.

Prof. Savvas Savvides (VIB-UGent): "We were surprised to find that both IL-23 and its receptor change drastically to create an intimate cytokine-receptor interface. In this interface, the receptor uses a functional hotspot on IL-23, enabling it to recruit an essential co-receptor for pro-inflammatory signaling. The binding site of the co-receptor on IL-23 also emerged as an unexpected finding. What we have now discovered about the pro-inflammatory complex mediated by IL-23 appears to be a new paradigm in the field."

Continued combined expertise

The researchers relied on integrative structural biology, combining methods to describe protein structures in atomic detail with complementary biochemical, biophysical, cellular and in vivo studies.

Prof. Savvides (VIB-UGent): "These initial research milestones from our program on IL-23 will be the cornerstone for further research in our own labs and elsewhere. After all, many questions still remain unanswered. For instance: how does IL-23 bind with other possible co-? Furthermore, our insights are expected to fuel the development of new therapeutic strategies against IL-23."

Explore further: Cytokine controls immune cells that trigger inflammatory bowel disease, study finds

More information: Yehudi Bloch et al. Structural Activation of Pro-inflammatory Human Cytokine IL-23 by Cognate IL-23 Receptor Enables Recruitment of the Shared Receptor IL-12Rβ1, Immunity (2017). DOI: 10.1016/j.immuni.2017.12.008

Related Stories

Cytokine controls immune cells that trigger inflammatory bowel disease, study finds

April 18, 2017
A certain cytokine, or small protein that helps cells communicate during immune responses, can control whether immune cells promote or suppress inflammatory bowel disease, a finding that could lead to new treatments, according ...

Researchers unravel viruses' strategies to dodge immune systems

November 7, 2016
As mammals evolve, so do mammalian viruses. In doing so, they develop creative and effective ways to counter and evade the antiviral responses of their mammal hosts' immune systems. Researching those mechanisms at the molecular ...

Autoimmune diseases increase cardiovascular and mortality risk

August 30, 2017
Researchers from the Hospital del Mar Medical Research Institute (IMIM) and IDIAP Jordi Gol have just published an article showing that autoimmune diseases significantly increase cardiovascular risk as well as overall mortality. ...

Research opens up new treatment route for inflammatory rheumatism

August 23, 2016
Enthesitis, inflammation of tendons where they attach to the bone, is a common medical problem which underlies various forms of inflammatory rheumatism. Although around 1% of the population is affected, the mechanisms driving ...

Recommended for you

Eczema drug effective against severe asthma

May 21, 2018
Two new studies of patients with difficult-to-control asthma show that the eczema drug dupilumab alleviates asthma symptoms and improves patients' ability to breathe better than standard therapies. Dupilumab, an injectable ...

Neuron guidance factor found to play a key role in immune cell function

May 21, 2018
Macrophages are white blood cells involved in a variety of biological functions, from destroying infectious pathogens to repairing damaged tissue. To carry out their different roles, macrophages must first be activated and ...

Immune cells hold promise in slowing down ALS

May 21, 2018
Recent research from Houston Methodist Hospital showed that a new immunotherapy was safe for patients with ALS and also revealed surprising results that could bring hope to patients who have this relentlessly progressive ...

First clues to the causes of multiple sclerosis

May 16, 2018
Multiple sclerosis, which affects one in 1,000 people, is frequently characterised by relapses associated with variable functional impairments including among others vision problems, impairment of locomotor functions or difficulties ...

A high-fiber diet protects mice against the flu virus

May 15, 2018
Dietary fiber increases survival in influenza-infected mice by setting the immune system at a healthy level of responsiveness, according to a preclinical study published May 15th in the journal Immunity. A high-fiber diet ...

Study finds that different diseases elicit distinct sets of exhausted T cells

May 15, 2018
The battle between the human immune system and long-term, persisting infections and other chronic diseases such as cancer results in a prolonged stalemate. Over time battle-weary T cells become exhausted, giving germs or ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.