Understanding inhibitory receptor function in neutrophils through the lens of CLEC12A

Abstract

The immune system uses innate and adaptive immune defense mechanisms to kill offending cells and organisms, eliminate cancer cells, and respond to endogenous danger signals, while limiting damage to self. 1 Thus, an immune system response, including that of neutrophils, must be tightly regulated in a context-dependent manner. This regulation requires systems that control the threshold to activating signals, the strength of the response, and the timing of response termination. 2 Neutrophils possess a combination of functions that enable them to respond rapidly and efficiently to signals generated by infection or cell injury. 3 They are capable of rapid mobility, are one of the most deformable of eukaryotic cells, and are highly proficient in phagocytosing foreign particles. Phagocytosis sequesters pathogens into restricted spaces away from normal tissue, termed phagolysosomes, where a toxic environment is created by introduction of antimicrobial peptides and proteases by fusion with intracellular granules, by hydrogen ion generation leading to a low pH, and by NADPH oxidase complex production of reactive oxygen species (ROS). These same antimicrobial agents can be directly released extracellularly or as constituents of neutrophil extracellular traps (NETs). Neutrophils are the first leukocytes recruited in large numbers from the circulation to a site of infection where these effector functions eradicate pathogens and contribute to tissue repair. 4 To avoid collateral damage that

Neutrophils and their friends

“…Mechanisms for regulating the threshold to activation provide a way to tune responses to meet demand, as achieved by interruption of intracellular activation pathways by engagement of inhibitory receptors. Using the C‐lectin inhibitory receptor CLEC12A as a model, Fernandes and McLeish discuss its cell biology to illustrate how inhibitory receptors contribute to the regulation of neutrophil responsiveness 4 . Many neutrophil receptors are members of the family of G protein‐coupled receptors, which participate in the full spectrum of responses, from activation to inhibition.…”