Understanding the Role of Antimicrobial Peptides in Neutrophil Extracellular Traps Promoting Autoimmune Disorders

Abstract

AMPs are small oligopeptides acting as integral elements of the innate immune system and are of tremendous potential in the medical field owing to their antimicrobial and immunomodulatory activities. They offer a multitude of immunomodulatory properties such as immune cell differentiation, inflammatory responses, cytokine production, and chemoattraction. Aberrancy in neutrophil or epithelial cell-producing AMPs leads to inflammation culminating in various autoimmune responses. In this review, we have tried to explore the role of prominent mammalian AMPs-defensins and cathelicidins, as immune regulators with special emphasis on their role in neutrophil extracellular traps which promotes autoimmune disorders. When complexed with self-DNA or self-RNA, AMPs act as autoantigens which activate plasmacytoid dendritic cells and myeloid dendritic cells leading to the production of interferons and cytokines. These trigger a series of self-directed inflammatory reactions, leading to the emergence of diverse autoimmune disorders. Since AMPs show both anti- and pro-inflammatory abilities in different ADs, there is a dire need for a complete understanding of their role before developing AMP-based therapy for autoimmune disorders.

Keywords: antimicrobial peptides; autoimmune disorders; cathelicidins; cytokines; defensins; neutrophil.

Figure 1

Representation of neutrophil extracellular trap formation through lytic and non-lytic NETosis pathways.

Figure 2

Role of antimicrobial peptides in promoting the pathogenesis of rheumatoid arthritis (RA). Neutrophil activation in joints leads to the production of cytokines and chemokines which further promote neutrophil recruitment and NETs formation. Activated NETs promote inflammation by producing cytokines such as TNF-α, IL-6, and IL-1β which then activate the production of HBD-2 and HBD-3. HBD-3 activates metalloproteinases which play an important role in cartilage destruction.

Figure 3

Antimicrobial peptides such as LL-37 and defensins facilitate the progression of systemic lupus erythematosus (SLE). Release of immunogenic complexes (self DNA + LL-37) from apoptotic neutrophils prompts the activation of pDCs via Toll-like receptors (TLR-9). Activated pDCs release type-1 IFN which further promotes NETosis. α-defensin secretion from activated neutrophils serves as a chemoattractant for immune cells, activating innate and adaptive immunity leading to the SLE condition.

Figure 4

Self-DNA/LL-37 and self-RNA/LL-37 promote the pathogenesis of psoriasis. Keratinocytes get activated under the pressure of tissue injury, infection, or genetic factors and express high levels of AMPs and nucleic acids, which form immunogenic complexes that activate pDCs or mDCs via Toll-like receptors (TLR9 or TLR8). Activated DCs produce type I IFN, TNF-α, and cytokines (IL-6, IL-12, IL-23) which promote NETosis. Activated neutrophils produce LL-37 and nucleic acids, thereby self-propagating the inflammatory cycle.