Ground-breaking insights into how inflammatory diseases work are reported by researchers from Queen’s University Belfast, in collaboration with an international team of experts. The findings could eventually lead to new treatments for a range of diseases caused by inflammation, including sepsis, Crohn’s disease, psoriasis and Multiple Sclerosis.
The team found that a protein called Pellino 2 plays an important role in how the body starts the inflammatory response.
“Inflammation is the body’s response to infection by disease-causing micro-organisms. This involves the movement of white blood cells, such as neutrophils, from blood vessels, into the infected tissue where they destroy the invading micro-organism.
However, the recruitment of neutrophils into tissues needs to be tightly controlled since prolonged tissue infiltration of these cells will lead to damage of normal healthy tissue. In the case of sepsis, we see inflammation spread rapidly throughout the body as a response to a bacterial infection in the blood, which can lead to life-threatening organ dysfunction,"
explained Professor Paul Moynagh, Professor of Immunology at the Wellcome-Wolfson Institute for Experimental Medicine at Queen’s University Belfast, who led the team.
The protein discovered by the researchers is involved in the triggering of the movement of white blood cells called neutrophils from blood vessels into the tissue that is infected by invading micro-organisms.
Pellino 2 is one of the three E3 ubiquitin ligases that have various regulatory roles in innate immune signaling pathways. Although progress has been made in defining the functions of Pellino 1 and Pellino 3, there is has been a lack of clarity into the physiological roles of Pellino 2 thus far.
[caption id=“attachment_95327” align=“aligncenter” width=“680”] Schematic representation of Pellino2 mediated NLRP3 inflammasome priming.
In wild type macrophages LPS promotes the association of Pellino 2 with NLRP3 and so facilitates ubiquitination of NLRP3.
This promotes NLRP3 inflammasome assembly, ASC oligomerization and downstream caspase-1-mediated processing of pro-IL-1β and pro-IL-18 and pyroptosis. Pellino2 also promotes ubiquitination of IRAK1 and so limits the interaction of IRAK1 with NLRP3 and prevents the inhibitory effects of IRAK1 on NLRP3 activation.
In Peli2−/− macrophages this braking effect of Pellino2 on IRAK1 is removed, allowing for IRAK1 to interact with NLRP3 and suppress downstream activation of the NLRP3 inflammasome
Credit: Fiachra Humphries, et al. CC-BY[/caption]
Neutrophils kill the infection, but if they linger for too long they can also damage healthy tissue. If a method can be found to effectively and safely block or control the protein, then it could in future be developed into a specific therapy.
The research team has already had success with stopping the protein in lab-based models and is now exploring molecules that could potentially be turned into a therapy.
Understanding Inflammatory Diseases
Inflammatory diseases are regarded as amongst some of the most difficult to treat, with sepsis in particular posing a critical challenge to frontline health care professionals. Understanding how the body promotes the migration of neutrophils into tissue may provide important clues for designing new drugs to control chronic inflammatory diseases such as sepsis.
Studies suggest that vulnerability to sepsis is on the rise around the world, as more people undergo invasive procedures or take immunosuppressive drugs to treat other chronic conditions, due to both aging populations and increased access to healthcare.
A global rise in resistance to antibiotics also has increased the risk of blood poisoning, driving a growth in sepsis cases.
“Our team at Queen’s University demonstrated that the Pellino 2 protein was involved in the production of molecules that promote inflammation during bacterial infection. Blocking this particular protein could therefore be a strategy to treat inflammatory diseases caused by bacteria. This is a key step forward in improving treatment and patient outcomes in a wide range of diseases. Inflammatory disease is prevalent, problematic and difficult to treat; understanding it is one of the most important challenges in medical research today,"
said Dr. Alice Dubois, Researcher at the Wellcome-Wolfson Institute for Experimental Medicine at Queen’s.
Financial support for the research came from the Science Foundation Ireland.
Fiachra Humphries, Ronan Bergin, Ruaidhri Jackson, Nezira Delagic, Bingwei Wang, Shuo Yang, Alice V. Dubois, Rebecca J. Ingram & Paul N. Moynagh The E3 ubiquitin ligase Pellino2 mediates priming of the NLRP3 inflammasome Nature Communications volume 9, Article number: 1560 (2018) doi:10.1038/s41467-018-03669-z
Top Image: Queen’s University Belfast