The role of neutrophil granule proteins in neuroinflammation and Alzheimer’s disease

Abstract

Neutrophils are the innate immune system’s first line of defense. Neutrophils play a critical role in protecting the host against infectious pathogens, resolving sterile injuries, and mediating inflammatory responses. The granules of neutrophils and their constituent proteins are central to these functions. Although neutrophils may exert a protective role upon acute inflammatory conditions or insults, continued activity of neutrophils in chronic inflammatory diseases can contribute to tissue damage. Neutrophil granule proteins are involved in a number of chronic inflammatory conditions and diseases. However, the functions of these proteins in neuroinflammation and chronic neuroinflammatory diseases, including Alzheimer’s disease (AD), remain to be elucidated. In this review, we discuss recent findings from our lab and others that suggest possible functions for neutrophils and the neutrophil granule proteins, CAP37, neutrophil elastase, and cathepsin G, in neuroinflammation, with an emphasis on AD. These findings reveal that neutrophil granule proteins may exert both neuroprotective and neurotoxic effects. Further research should determine whether neutrophil granule proteins are valid targets for therapeutic interventions in chronic neuroinflammatory diseases.

A peripheral neutrophil-related inflammatory factor predicts a decline in executive function in mild Alzheimer’s disease

“…The marker with the highest factor loading on the latent variable was NGAL, also known as lipocalin-2. NGAL is a pro-inflammatory molecule selectively secreted in neutrophil granules [4]. It is secreted into peripheral circulation by neutrophils and endothelial cells, and it prevents the growth of bacterial colonies [19,33].…”

“…MPO, an enzyme found mainly in the azurophilic granules of neutrophils, produces reactive oxygen species upon neutrophil degranulation [4,18]. It has been found in increased concentrations in the plasma of patients with AD [37] and elevated levels of both MPO, and oxidative products have been reported in the cortex and hippocampus in AD brains ( [38]).…”

“…Recent studies suggest a role of innate immune activity, including the effects of neutrophils, in neurodegeneration related to AD [4,5]. Neutrophils are involved in inflammation, pathogen clearance via phagocytosis, generation of reactive oxygen species (ROS) via myeloperoxidase activity, and neutrophil extracellular traps (NETs) [4]. Neutrophil activation and related oxidative stress have been associated with AD pathology in humans [5][6][7].…”

“…The present study examines five neutrophil-related plasma markers in peripheral blood: myeloperoxidase (MPO) which is responsible for neutrophil-related oxidative stress [4,18], neutrophil gelatinase-associated lipocalin (NGAL) a neutrophil secreted anti-microbial molecule [4,19], tumor necrosis factor (TNF) which is involved in neutrophil activation and survival [20,21], and interleukin-8 (IL-8) and macrophage inflammatory protein-1β (MIP-1β), which both play a role in neutrophil trafficking and activation and which are both secreted by activated neutrophils [22].…”

Antimicrobial Peptides Derived from the Immune Defense Protein CAP37 Inhibit TLR4 Activation by S100A9

“… 20 – 22 Interestingly, we previously identified RAGE as a direct binding partner and potential receptor for CAP37 and showed that NE and CG could also interact with this receptor. 15 , 23 Here, we investigated whether CAP37, NE, and CG could interact with TLR4. To perform these in vitro binding experiments, we used a complex between TLR4 and the extracellular protein MD-2, which forms the functional pattern recognition receptor.…”