Free and complexed-secretory immunoglobulin A triggers distinct intestinal epithelial cell responses

Abstract

SummarySecretory immunoglobulin A (SIgA) antibodies play an important role in protecting the mucosal surfaces against pathogens and maintaining homeostasis with the commensal microbiota. Because a substantial portion of the gut microbiota is coated with SIgA, we hypothesized that microbiota–SIgA complexes are important for the maintenance of gut homeostasis. Here we investigated the relationship between microbiota–SIgA complexes and inflammatory epithelial cell responses. We used a multi‐cellular three‐dimensional (3D) organotypical model of the human intestinal mucosa composed of an intestinal epithelial cell line and primary human lymphocytes/monocytes, endothelial cells and fibroblasts. We also used human SIgA from human colostrum, and a prominent bacterial member of the first colonizers, Escherichia coli, as a surrogate commensal. We found that free and microbiota‐complexed SIgA triggered different epithelial responses. While free SIgA up‐regulated mucus production, expression of polymeric immunoglobulin receptor (pIgR) and secretion of interleukin‐8 and tumoir necrosis factor‐α, microbiota‐complexed SIgA mitigated these responses. These results suggest that free and complexed SIgA have different functions as immunoregulatory agents in the gut and that an imbalance between the two may affect gut homeostasis.

Unraveling the Differences between Gram-Positive and Gram-Negative Probiotics in Modulating Protective Immunity to Enteric Infections

“…Previous studies have shown the involvement of IgA in moderating inflammatory responses through modulating dendritic cells and regulatory T cell functions (61, 62). Further, secretory IgA-commensal complexes were shown to reduce inflammatory responses in intestinal epithelial cells (63). Thus, the role of secretory IgA in mitigating infection-induced inflammatory responses is intriguing and requires further investigation.…”

Modeling Host-Pathogen Interactions in the Context of the Microenvironment: Three-Dimensional Cell Culture Comes of Age

“…It was the first technology used to develop 3-D models for infection studies with bacterial (Salmonella) and viral (rhinovirus) pathogens (11,51). A range of RWV-derived 3-D models have been developed using cell lines, stem cells, and/or primary cells, including small and large intestine (11,80,141,143,145,146,152,(168)(169)(170)(171)(172)(173)(174)(175)(176)(177), lung (144,147,(178)(179)(180)(181)(182), liver (148,153,174,183,184), bladder (8,(185)(186)(187), reproductive tissue (149)(150)(151)(188)(189)(190), heart (191)(192)(193), prostate (142,186,194), pancreas (195,<...>…”

“…1B, panel d), polarization, appropriate expression/ localization of adherens/tight junctional complexes, metabolic product secretion, gene expression, cytokine production, responses to antimicrobials and microbial products, support of commensals, and/or susceptibility to infection (8, 11, 80, 141-153, 168-194, 197-208). In addition, RWV models have been advanced to incorporate immune cells to study their role in host-microbe interactions (171,175,177,180).…”

“…We began using the RWV to engineer 3-D models of human intestine for infection studies in the late 1990s after realizing that available models for studying bacterial pathogenesis lacked multiple aspects of the in vivo microenvironment (11). RWV-derived 3-D models have enabled the study of hostmicrobe interactions relevant to different regions of the intestinal tract, including the small intestine (11,169) and colon (80,143,145,146,152,171,172,175,177). Imaging of these models revealed enhanced 3-D architecture relative to monolayers, including the presence of extensive 3-D folds and microvilli, that more closely resembled what is observed in vivo ( Fig.…”

“…These 3-D models are essentially "inside-out" such that the apical/luminal side faces the media and the basal side faces the scaffold, allowing for straightforward introduction of pathogens, toxins, and antimicrobials at the apical surface, as commonly occurs in vivo. Collectively, these models have shown physiologically relevant expression and localization of key cellular components, including junctional proteins (e.g., ZO-1, occludin, symplekin, E-cadherin, ␤-catenin, and desmosomes), secretion of basal lamina components (e.g., collagen types II, III, and IV, laminin, vimentin, and fibronectin), brush border formation with villin, and/or mucus secretion (11,80,143,145,146,152,169,171,172,175,177). Spontaneous cellular differentiation into multiple lineages found in the intestinal epithelium is also observed, including enterocytes, M cells, goblet cells, and/or Paneth cells (enteroendocrine cells were not evaluated) (11,80,146,152,171,175).…”