Anti-Inflammatory Role for Intracellular Dimeric Immunoglobulin A by Neutralization of Lipopolysaccharide in Epithelial Cells

Abstract

Intestinal epithelial cells (IEC) play a central role in innate and acquired mucosal immunity. They ensure early signaling to trigger an inflammatory response against pathogens. Moreover, IEC mediate transcytosis of dimeric IgA (dIgA), through the polymeric-immunoglobulin receptor (pIgR), to provide secretory IgA, the major protective Ig in mucosal secretions. Using an in vitro model of polarized IEC, we describe an additional anti-inflammatory mechanism of dIgA-mediated protection against intracellular bacterial components involved in the proinflammatory activation of IEC. Specific dIgA colocalizes to lipopolysaccharide (LPS) in the apical recycling endosome compartment, preventing LPS-induced NF-kappaB translocation and subsequent proinflammatory response. Thus, intracellular neutralization by dIgA limits the acute local inflammation induced by proinflammatory pathogen-associated molecular patterns such as LPS.

Long-Term Exposure of the HT-29 Human Intestinal Epithelial Cell Line to TNF Causes Sustained Up-Regulation of the Polymeric Ig Receptor and Proinflammatory Genes through Transcriptional and Posttranscriptional Mechanisms

“…We postulate that up-regulation of pIgR-mediated IgA transport by TNF contributes both to immune defense and to the regulation of inflammatory responses, for example by neutralizing LPS in the intestinal lumen (42) and within epithelial cells (7). By contrast, chronic exposure of the intestinal epithelium to TNF has been implicated in the pathogenesis of inflammatory bowel diseases (12,26,27), and therapeutic agents that neutralize TNF activity have proven effective in the treatment of these conditions (43).…”

“…This transport mechanism provides three tiers of immune protection by excreting IgA-containing immune complexes across the epithelium, neutralizing viruses and perhaps other microbes within epithelial cells, and releasing secretory IgA at the epithelial surface, where it serves as an external barrier (6). A novel anti-inflammatory function for IgA has been suggested by the demonstration that IgA can neutralize LPS within intestinal epithelial cells during pIgR-mediated transport (7). Secretory component, the cleaved extracellular domain of pIgR, further contributes to intestinal defense and homeostasis by acting as a nonspecific microbial scavenger and by limiting inflammatory processes (8).…”

Roundtrip Ticket for Secretory IgA: Role in Mucosal Homeostasis?

“…IgA functions at three anatomical levels in relation to mucosal epithelium: 1) luminal SIgA Ab prevents adhesion and entry of Ag into the epithelium (38); 2) IgA Ab in the lamina propria binds and excretes Ag to the lumen (39); and 3) IgA Ab in transit through the epithelium can inhibit virus production (40) or neutralize proinflammatory Ags (41). An additional property of IgA is its inability to trigger the release of inflammatory mediators through receptors specific for its Fc domain (42)(43)(44).…”

Dysfunctions of the Iga system: a common link between intestinal and renal diseases

“…14 In addition to controlling pathogens and commensals, IgA antibodies inside epithelial cells neutralize microbial products that have proinflammatory activity, such as lipopolysaccharide. 4 Hence, IgA can play a role both at normal conditions and in infection.…”

“…3 Serum Iga, the second most abundant isotype in circulation, consists mainly of monomers produced by bone marrow plasma cells, 1 whereas secretory Iga (SIga) molecules are synthesized as dimers by local plasma cells before being transported to mucosal surfaces via epithelial cells, based on their interaction with the polymeric Ig receptor (pIgR). 4 Signals delivered by monomeric serum Iga (mIga) are essential in controlling the immune system by preventing the development of autoimmunity and inflammation. Polymeric Iga (pIga) participates in immune responses by induc ing the activation of eosinophils, neutrophils, monocytes and macro phages.…”