Hyper inflammation compromises pathogen-clearing ability, also destroys the tissues surrounding the inflamed area

Researchers at the Indian Institute of Technology (IIT) Kanpur have identified and characterised a novel small protein molecule that can effectively control inflammation leading to better treatment outcomes. In contrast, inflammation control by molecules that are undergoing clinical trials may not be optimal due to inherent drawbacks. The work was done in collaboration with the University of Queensland.

Hyper inflammation

While some amount of inflammation at the site of infection is required for effective clearance of pathogens, too much inflammation compromises pathogen-clearing ability. Hyper inflammation also destroys the tissues surrounding the inflamed area leading to inflammation disorders such as sepsis, inflammatory bowel syndrome, rheumatoid arthritis and psoriasis.

A small protein (C5a) that is a part of the innate immunity (immediate defence against pathogens that have never been encountered before) gets activated when a pathogen enters the body. The C5a protein then binds to a particular receptor (C5aR1) found on the surface of certain cells such as macrophages and neutrophils to begin the process of inflammation and pathogen clearance.

Neutrophiles are already present in the body and circulate in the blood. Once the small protein binds to the C5aR1 receptor found on neutrophils, there is increased migration towards the site of infection leading to hyper inflammation. At the same time, binding of the small protein to the receptor on macrophages reduces the amount of a pro-inflammatory cytokine called interleukin-6 (IL-6) that is released, which is desirable to overcome inflammatory symptoms.

Therapeutic agents now undergoing clinical testing prevent the C5a protein from binding to the receptor found on neutrophils leading to reduced migration of neutrophils to the site of infection. Hyper inflammation is thus prevented. However, it has the opposite effect on interleukin-6 release. Unlike the C5a protein, the drug candidate molecules do not reduce the amount of IL-6 being released thereby causing more inflammation.

Role of IL-6

“There is more inflammation when the amount of IL-6 at the site of infection is more. So it is desirable to reduce the amount of IL-6 being released to overcome the inflammatory symptoms,” says Arun Shukla from the institute’s Department of Biological Sciences and Bioengineering. He is one of the corresponding authors of a paper published in the Journal of Biological Chemistry.

The small protein molecule identified by IIT Kanpur researchers addresses the shortcomings seen with the drug molecules now undergoing clinical testing. The drug molecule that IIT Kanpur team used for this study is already known to bind to the C5aR1 receptor. But its effects were not characterised in term of IL-6 release and neutrophil migration.

“Our peptide molecule binds to the C5aR1 receptor found on neutrophils and reduces their migration to the site of infection. And unlike the molecules now being tested, our peptide molecule also reduces the amount of IL-6 being released,” says Prof. Shukla. Under in vitro conditions, the combined effect may lead to reduced inflammation.

“The molecule only reduces and not blocks neutrophil migration. There should be sufficient inflammation at the infection site to clear the pathogens,” says Shubhi Pandey from IIT Kanpur and first author of the paper.

The peptide molecule identified by the team is smaller than the C5a protein so the binding to the receptor is weak. “So we have to use higher concentration of our synthetic peptide to achieve better results. Future work would be to increase the strength of binding by improving the molecule so that less concentration is needed,” Prof. Shukla says. The team plans to carry out animal studies in future to measure the therapeutic potential of the molecule.