Jeon JH, et al. Immune Netw. 2020 Nov;20(6):e46. https://doi.org/10.4110/in.2020.20.e46

Rationale: Neutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. Objectives: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia. Methods: Neutrophils were isolated from patients with sepsis and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of reactive oxygen species generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. Measurements and Main Results: Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET-dependent mechanism. Conclusions: These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis.

Hong CW. Immune Netw. 2017 Oct;17(5):298-306. https://doi.org/10.4110/in.2017.17.5.298

We previously reported the protective effects of long-term administration of ferulic acid against the in vivo toxicity of β-amyloid peptide administered intracerebroventricularly in mice. In the present study, we investigated the effects of ferulic acid in transgenic amyloid precursor protein (APP)swe/presenilin 1 (PS1)dE9 (APP/PS1) mouse model of Alzheimer disease (AD). Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.

Neutrophils are the first-line defense against microbes. Enhancing the microbicidal activity of neutrophils could complement direct antimicrobial therapy for controlling intractable microbial infections. Previously, we reported that lysophosphatidylcholine (LPC), an endogenous lipid, enhances neutrophil bactericidal activity (Yan et al. 2004. Nat. Med. 10: 161–167). In this study we show that LPC enhancement of neutrophil bactericidal activity is dependent on glycine, and is mediated by translocation of intracellularly located glycine receptor (GlyR) α2 to the plasma membrane, and subsequent increase in azurophil granule-phagosome fusion/elastase release. LPC induced GlyRα2-mediated [Cl⁻]_i increase, leading to transient receptor potential melastatin (TRPM)2-mediated Ca²⁺ influx. Studies using human embryonic kidney 293 cells heterologously expressing TRPM2 and neutrophils showed that TRPM2 channel activity is sensitive to [Cl⁻]_i. Finally, LPC induced p38 MAPK phosphorylation in an extracellular calcium/glycine dependent manner. SB203580, a p38 MAPK inhibitor, blocked LPC-induced enhancement in Lucifer yellow uptake, azurophil granule-phagosome fusion, and bactericidal activity. These results propose that enhancement of azurophil granule-phagosome fusion via GlyRα2/TRPM2/p38 MAPK signaling is a novel target for enhancement of neutrophil bactericidal activity.