CLEC5A proved to be a key player that triggers NET formation (NETosis) after bacterial infections

Years of CLEC5A study has successfully proved its heavy involvement in inflammation of Dengue fever and Avian flu patients, and is the lethal factor in dengue hemorrhagic shock syndrome. However, Dr. Edmond Hsieh was not satisfied with such pioneering findings, and he has been challenged with a very tough question ‘What is the physiological functions of CLEC5A in host defense mechanism?’ Does activation of CLEC5A not bring beneficial effect in microbial infection?

He seems to have found the answer! Lately, in the ‘Nature Communications’ Journal, his team proposed a more logical and important new role for CLEC5A. In the article, “CLEC5A is a critical receptor in innate immunity against Listeria infection”, they pointed out CLEC5A could be playing a more crucial role compared to the famous toll-like receptor 2 (TLR2) during the course of bacterial infections. Dr. Hsieh’s group find that CLEC5A is highly expressed in neutrophil, which is the major player to eat up the ‘bad intruders’. When a person is infected by bacteria to a magnitude that neutrophils can’t swallow effectively, the suicidal mode will be turned on and its nucleus will be expanded due to the loosening of DNA via the activation of PAD4 kinase. DNA segments are long and sticky, and work like a trapping net that can grab a chunk of the bacteria and disable them. This process is called ‘Neutrophil Extracellular Trap’, and is referred to as NET in short.

 

 

The original design of CLEC5A is o destroy the invaders with no reservations. Sadly, it turned out the dysregulated NET formation also causes damages, even after the invaders are eliminated. The problem is, after the bacteria are cleaned, NET lingers on create more problems to the human body due to overproduction of interferon-alpha released from NET-stimulated plasmacytoid dendritic cells (pDCs). As a matter of fact, many auto immune diseases appear after patients had an infectious history, and one of the best examples is that most of Systemic lupus erythematosus patients have infection history prior to appearance of clinical symptoms of Lupus. Usually, interferon-alpha serum level is very high, and activated PAD4 with drastic drop of neutrophils (known as leukocytopenia) were noted in SLE patients.

Hsieh’s team took a systematic approach by testing Listeria on a variety of gene knock-out mice. Result shows only mice of the ELEC5A gene is depleted group showed no sign of NET, neither PAD4 is activated. PAD4 has been shown to play a critical factor to loosen DNA from supercoiled form, and is the first step for nucleus expansion and DNA release.

 

 

The story does not end here. Compared to wild type (WT) littermates, the expression of IL-1β, TNF and IL-17A is down regulated in the CLEC5A knock-out mice. Moreover, the livers of CLEC5A lacking mice develop severe damaging associated with disappearance of IL-17A+ γδ T cells, which play critical role in mucosal immunity of intestine. As overproduction of IL17A is the signature of the inflammatory bowel disease (IBD), blockade of CLEC5A may be applied for the treatment of IBD.

When Toll-like receptor TLR2 was identified, scientists thought TLR2 are the most important innate immunity receptor against Gram-positive bacteria. It was realized later that it may not be that simple. The role of CLEC5A in NET has opened up a new passage in finding best resolutions treating bacterial infections.

 

 

Dr. Hsieh expressed his commitment in finding all possible relations with NET and bacteria. By identifying a clear picture, much effective therapeutics can be developed.

The paper can be viewed on line at Nature Communications website: https://www.nature.com/articles/s41467-017-00356-3.

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