IgA Enhances NETosis and Release of Neutrophil Extracellular Traps by Polymorphonuclear Cells via Fcα Receptor I

Abstract

Polymorphonuclear cells (neutrophils) are the first cells that arrive at sites of infections. According to the current dogma, they are involved in eliminating bacteria, after which they die through apoptosis. We now demonstrate that enhanced IgA-induced phagocytosis of bacteria or beads by neutrophils led to increased cell death. Nuclear changes and positivity for the general cell death marker 7-aminoactinomycin D were observed, but the absence of annexin V membrane staining supported that neutrophils did not die via apoptosis, in contrast to neutrophils that had not phagocytosed bacteria. Moreover, increased release of neutrophil extracellular traps (NETs) was observed, which was most likely due to augmented production of reactive oxygen species after uptake of IgA-opsonized particles. Blocking the IgA Fc receptor FcαRI abrogated phagocytosis and NET formation. Thus, FcαRI triggering on neutrophils resulted in a rapid form of cell death that is referred to as NETosis, as it is accompanied by the release of NETs. As such, IgA may play a prominent role in mucosal inflammatory responses, where it is the most prominent Ab, because it enhanced both phagocytosis of bacteria and formation of NETs, which are effective mechanisms that neutrophils employ to eliminate pathogens.

Human IgA Fc Receptor FcαRI (CD89) Triggers Different Forms of Neutrophil Death Depending on the Inflammatory Microenvironment

“…Furthermore, we showed that this nonapoptotic form of cell death, in the absence of bacteria, does not induce proinflammatory responses; rather, it promotes an anti-inflammatory cytokine microenvironment in coculture with macrophages. In the presence of bacteria, NETosis induced by IgA-opsonized particles appears to enhance immune defense (21). Conversely, our data suggest that, in the absence or following elimination of bacteria, the enhanced susceptibility of activated neutrophils to anti-inflammatory death induced by endogenous IgA or by FcaRI-targeting agents may accelerate the resolution of inflammation, even under antiapoptotic inflammatory conditions.…”

“…Aleyd et al (21) recently reported that phagocytosis of IgAopsonized bacteria resulted in neutrophil ROS production, release of DNA NETs, and subsequent neutrophil death by a nonapoptotic form of death (NETosis). In a scenario in which pathogens are still present, the induction of NETosis by IgA-opsonized bacteria might prevent counterproductive anti-inflammatory signals in macrophages by other forms of cell death, including apoptosis (21). In contrast, subsequent to pathogen elimination, clearance of activated neutrophils by apoptosis, or another anti-inflammatory form of cell death, is essential to prevent excessive inflammation and tissue damage.…”

“…Schettini et al (20) described that immobilized, but not soluble IgA, promotes neutrophil death. Similarly, it was shown recently that IgA-opsonized bacteria induced a rapid form of neutrophil death that is associated with NET formation and referred to as "NETosis" (21). Notably, Schettini et al (20) reported that promotion of neutrophil death by immobilized IgA was almost completely prevented by blocking Abs directed to CD18 or CD11b, indicating that Mac-1 (CR3, CD11b/ CD18) signaling is essential for the transmission of death signals.…”

Immunoglobulin A: magic bullet or Trojan horse?

“…Stimulation of neutrophils by IgA-immune complexes, however, induces multiple proinflammatory functions, including phagocytosis, antibodydependent cellular cytotoxicity (ADCC), degranulation, release of cytokines and chemokines, production of reactive oxygen species (ROS) and the release of NETs (Fig. 1b) [4,7]. Previously, our group showed that FcaRI triggering leads to the release of the chemoattractant leukotriene B4 (LTB4), thereby inducing neutrophil migration and recruitment [8].…”

Immune defence mechanisms of barramundi (Lates calcarifer) peripheral blood against Streptococci

“…Immune components such as IgA, an important mucosal antibody, also trigger NET formation, which has been attributed to ROS production when opsonised particles are engulfed (Aleyd et al, 2014). Complement C5a in conjunction with cytokines, such as Interferon Alpha (IFN-) or Granulocyte-macrophage colonystimulating factor (GM-CSF), may also activate NETs, though these NETs are of a mitochondrial DNA source (Yousefi et al, 2009) PAMPs exist for identifying DNA, RNA, fungi, protozoa and cancer proteins.…”