Neutrophil Extracellular Traps and Their Possible Implications in Ocular Herpes Infection

Abstract

Neutrophil extracellular traps (NETs) are net-like structures released from neutrophils. NETs predominantly contain cell-free deoxyribonucleic acid (DNA) decorated with histones and neutrophil granule proteins. Numerous extrinsic and intrinsic stimuli can induce the formation of NETs such as pathogens, cytokines, immune complexes, microcrystals, antibodies, and other physiological stimuli. The mechanism of NETosis induction can either be ROS-dependent or independent based on the catalase producing activity of the pathogen. NADPH is the source of ROS production, which in turn depends on the upregulation of Ca2+ production in the cytoplasm. ROS-independent induction of NETosis is regulated through toll-like receptors (TLRs). Besides capturing and eliminating pathogens, NETs also aggravate the inflammatory response and thus act as a double-edged sword. Currently, there are growing reports of NETosis induction during bacterial and fungal ocular infections leading to different pathologies, but there is no direct report suggesting its role during herpes simplex virus (HSV) infection. There are innumerable independent reports showing that the major effectors of NETosis are also directly affected by HSV infection, and thus, there is a strong possibility that HSV interacts with these facilitators that can either result in virally mediated modulation of NETosis or NETosis-mediated suppression of ocular HSV infection. This review focuses on the mechanism of NETs formation during different ocular pathologies, with its prime focus on highlighting their potential implications during HSV ocular infections and acting as prospective targets for the treatment of ocular diseases.

Rapid NETosis Is an Effector Mechanism to Combat Ocular Herpes Infection

“…The latter has been previously implicated in bacterial sepsis, fungal infections, autoimmune disorders, and cancer but not in HSV-1 infection. 11 We also made a striking observation that HSV-1 induced rapid NETosis occurs within the first hour of infection, which is much faster than the conventional NETosis induced by PMA, which takes about 4 hours. 25 This suggests that HSV-1 triggers a distinct mechanism of NETosis that involves a rapid release of chromatin without extensive decondensation or degradation.…”

“…On one hand, NETs could act as a physical barrier to prevent viral spread and as a source of antimicrobial peptides to kill or inhibit viral replication. 11 On the other hand, NETs could also cause collateral damage to the host tissue by inducing inflammation, oxidative stress, and apoptosis. To address this question, we depleted neutrophils from the cornea using Ly6G antibodies before infecting mice with HSV-1.…”

“…Emerging insights denote a correlation between neutrophil extracellular trap formation (NETosis) and bacterial and fungal ocular infections, underscoring a potential interplay between HSV-1 and NETosis or NETosis-associated modulation of HSV infection. 11 Herpesviruses, despite their immune-evasive capabilities, are discernible by the innate immune system, implicating inflammasomes in innate immune activation. These intracellular protein complexes are integral in the mediation of inflammatory responses, catalyzing the cleavage and subsequent activation of pro-inflammatory cytokines and gasdermin family proteins.…”

Exploring Heparanase Levels in Tears: Insights From Herpes Simplex Virus-1 Keratitis Patients and Animal Studies

“…It is presumed that there might be neutrophil infiltration to the site of the infection, which releases neutrophil extracellular traps (NETs) as a primary defense mechanism against the infection. 37 Studies have shown the NETs play a role in fungal and bacterial ocular infections, as well as in viral infections such as influenza virus and SARS–CoV-2. 38 – 41 However, their role in ocular HSV-1 infections remains a mystery.…”

The perspectives of NETosis on the progression of obesity and obesity-related diseases: mechanisms and applications

“…In the human immune system, NETosis is a double-edged sword. On the one hand, NETosis has been described as a neutrophil defense mechanism of the organism that traps and destroys a wide range of pathogens involved in anti-inflammatory, antibacterial and antiviral immune responses, including Gram-positive bacteria ( von Kockritz-Blickwede and Winstel, 2022 ), Gram-negative bacteria and their virulence factors ( Sung et al, 2022 ), fungi ( Huang et al, 2022 ), protozoa ( Conejeros et al, 2022 ) and viruses ( Kapoor and Shukla, 2023 ). NETosis is also involved in the normal regeneration and repair of blood vessels.…”