Research & Development

Science of NETosis 

Neutrophils are our body’s first line of pathogen defense and can use numerous strategies to protect it against infection. One response is the release of extracellular complexes primarily composed of decondensed chromatin and granular proteins. These complexes have been termed neutrophil extracellular traps (NETs) and the process of neutrophil rupture and cell death to release NETs has been designated NETosis.

The process of NETosis

The importance of close control of NETosis became clear in recent years as researchers identified that aberrant release and impaired degradation leads to sustained presence of pro-inflammatory NETs in tissue which is associated with variety of inflammatory diseases.

NETosis is a highly organized process that can be separated into distinct stages: 1) chromatin reorganization within the nucleus, 2) breaching of the nuclear membrane followed by chromatin decondensation within the cytoplasm, and 3) plasma membrane rupture leading to chromatin release and diffusion into the extracellular space.

The highly organized stages of NETosis

NETs in acute and chronic inflammatory diseases

The association of elevated NETs and active inflammatory disease has been described in a growing list of acute and chronic inflammatory diseases, including RA, HS, vasculitis, SLE, gout, sepsis, respiratory and cardiovascular diseases. The detrimental role of NETs in disease is a consequence of several elements with NETs being pro-inflammatory, cytotoxic to surrounding tissue, a source of autoantigens, and diverting the differentiation of cells often with pathogenic phenotypes. As a consequence, the reduction of NET levels in inflamed tissue has become a therapeutic approach of increasing interest for the treatment of inflammatory diseases.

Citryll is a leader in developing novel therapeutics that target NET driven inflammation by specifically targeting citrullinated histones, a characteristic feature of NETs, with the therapeutic monoclonal antibody, CIT-013. The anti-inflammatory effect of CIT-013 has been successfully demonstrated in numerous preclinical models and inhibition of NET release has been demonstrated in an LPS challenge study in healthy volunteers.

The pathogenic role of NETs