The proper functioning of the immune system is based on a fine balance between activation and inhibition. Immune suppression leads to the threat of infection by pathogens and immunodeficiency, while insufficient inhibition can lead to damage to self or autoimmunity. Inhibitory immune receptors play a crucial role in this balance.
Neutrophils are useful but also dangerous cells. They are essential to protect the host against invading pathogens and have the ability to quickly enter the tissues. However, their activity also causes collateral tissue damage that in ultimo can result in destruction of the tissue architecture and the formation of pus, also in non-infectious inflammatory conditions. Next to phagocytosis and degranulation, neutrophils fight bacteria through neutrophil extracellular traps (NETs), which arise from the release of the neutrophil's nuclear content into the extracellular space and consist of decondensed DNA decorated with antimicrobial proteins. Despite the importance of NETs in host defense, NETs contribute to pathology by several mechanisms. It is suggested that the DNA and antimicrobial peptides of NETs can be recognized by B cells which leads to the production of auto-antibodies, such as in SLE. Furthermore, the antimicrobial peptides attached to the NETs have poor target specificity, which leads to the damage of the tissues surrounding the NET. Finally, NETs have recently been shown to form a platform for platelets and form a central role in thrombosis. Therefore, NET formation contributes to pathology in several diseases that involve tissue infiltration by neutrophils.
We recently identified Signal Inhibitory Receptor on Leukocytes-1 (SIRL-1) as a negative regulator of human neutrophil function. SIRL-1 ligation inhibits the oxidative burst and prevents the pathogenic release of NETs in SLE. SIRL-1 engagement can dampen spontaneous and anti-neutrophil antibody-induced NET formation in SLE. This opens up the interesting therapeutic opportunity of inhibiting collateral damage by engagement of inhibitory receptors.
Disclosure of Interest None declared
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