Extracellular Traps in Inflammation: Pathways and Therapeutic Targets

Abstract

New roles for immune cells, overcoming the classical cytotoxic response, have been highlighted by growing evidence. The immune cells, such as neutrophils, monocytes/macrophages, and eosinophils, are versatile cells involved in the release of web-like DNA structures called extracellular traps (ETs) which represent a relevant mechanism by which these cells prevent microbes' dissemination. In this process, many enzymes, such as elastase, myeloperoxidase (MPO), and microbicidal nuclear and granule proteins, which contribute to the clearance of entrapped microorganisms after DNA binding, are involved. However, an overproduction and release of ETs can cause unwanted and dangerous effects in the host, resulting in several pathological manifestations, among which are chronic inflammatory disorders, autoimmune diseases, cancer, and diabetes. In this review, we discuss the release mechanisms and the double-edged sword role of ETs both in physiological and in pathological contexts. In addition, we evaluated some possible strategies to target ETs aimed at either preventing their formation or degrading existing ones.

Keywords: ETosis; ETs; NETosis; NETs; immunity; inflammation; neutrophils; pharmacological approach; strategies; therapies.

Figure 1

ETosis process in PMNs: lethal and vital NETosis. (A) Different stimuli activate neutrophils: cytokines, chemical compounds, and bacteria. (B) Activated white blood cells react by changing the structure of the nuclear membrane and start to lose their integrity. (C) Release of NETs in the extracellular space with the consequent cell death (Lethal NETosis). (D) Formation of vesicles containing DNA after the rupture of the nuclear membrane. (E) Migration of vesicles with entrapped DNA to the cell membrane and NETs release, leaving the cell alive (vital NETosis). Image created with BioRender 2025.

Figure 2

Molecular events of lethal NETosis. TLRs = Toll-like receptor; PAD4 = peptidyl arginine deiminase 4; LL-37 = human antimicrobial peptide; MPO = myeloperoxidase; NE = neutrophil elastase. Image created with BioRender 2025.