Dying and Necrotic Neutrophils Are Anti-Inflammatory Secondary to the Release of α-Defensins

Abstract

Neutrophils are recruited to sites of injury but their timely removal is thought to be vital to prevent exacerbating inflammation. In addition, the recognition of apoptotic cells by cells of the innate immune system provides potent anti-inflammatory and anti-immunogenic signals. In this paper we describe how human neutrophils dying by apoptosis or necrosis release anti-inflammatory peptides, the alpha defensins. This family of small cationic peptides, effectively inhibits the secretion of multiple pro-inflammatory cytokines and nitric oxide from macrophages, the main innate immune cell found at sites of chronic inflammation. In addition, the systemic administration of necrotic neutrophil supernatants and alpha defensins protects mice from a murine model of peritonitis. Hence their effects may be far reaching and serve to kill microbes whilst regulating a potentially tissue destructive inflammatory response.

Neutrophil-derived alpha defensins control inflammation by inhibiting macrophage mRNA translation

“…We have previously shown that although alpha defensins augmented the macrophage's ability to kill intracellular Pseudomonas aeruginosa, these peptides simultaneously inhibited the production of multiple cytokines (TNFα, IL-6, IL-8, and IL-1β) (5). HNP1 also inhibited TNFα biosynthesis from HMDMs stimulated with the toll-like receptor 7/8 (TLR7/8) agonist R848 (Fig.…”

“…We previously reported that the human antimicrobial peptides α-defensins [which are released following apoptosis, necrosis, or NET-osis (4) of neutrophils] also inhibited the secretion of multiple cytokines from activated HMDMs for up to 72 h, with full recovery thereafter and no effect on cell viability (5). In vivo, in mice, neutrophil derived α-defensins, given at the time of inducing peritonitis, led to a diminished inflammatory exudate (5). In addition, mice infected with pathogenic Salmonella enterica serovar Typhimurium showed a reduced bacterial load and serum TNFα levels upon administration of exogenous α-defensin.…”

Neutrophil Viability as a Clinical Outcome Marker in Mechanically Ventilated Critically Ill Trauma Patients: A Case Series

“…These findings were later challenged by Miles et al [9] who described α-defensins as active anti-inflammatory factors released by apoptotic/necrotic neutrophils, as shown in their studies. Their data showed that necrotic human neutrophils are in fact, anti-inflammatory, thus, neutrophil necrosis at sites of inflammation initiates its resolution rather than trigger it.…”

Human Defensins: Potential Tools for Clinical Applications

“…Furthermore, defensins cross-regulate pro-inflammatory cytokines and chemokines [4,14]. Alpha-defensins released from necrotic neutrophils are able to repress the secretion of various cytokines from macrophages, thus exhibiting anti-inflammatory effects [55]. Enhanced secretion of TNF-α or interferon-γ (IFN-γ) from neutrophils has been demonstrated to be caused by HNP1-3, thereby inducing increased phagocytotic activity of human macrophages [56].…”