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Intestinal Serum amyloid A suppresses systemic neutrophil activation and bactericidal activity in response to microbiota colonization.

ABSTRACT: The intestinal microbiota influences the development and function of myeloid lineages such as neutrophils, but the underlying molecular mechanisms are unresolved. Using gnotobiotic zebrafish, we identified the immune effector Serum amyloid A (Saa) as one of the most highly induced transcripts in digestive tissues following microbiota colonization. Saa is a conserved secreted protein produced in the intestine and liver with described effects on neutrophils in vitro, however its in vivo functions remain poorly defined. We engineered saa mutant zebrafish to test requirements for Saa on innate immunity in vivo. Zebrafish mutant for saa displayed impaired neutrophil responses to wounding but augmented clearance of pathogenic bacteria. At baseline, saa mutants exhibited moderate neutrophilia and altered neutrophil tissue distribution. Molecular and functional analyses of isolated neutrophils revealed that Saa suppresses expression of pro-inflammatory markers and bactericidal activity. Saa's effects on neutrophils depended on microbiota colonization, suggesting this protein mediates the microbiota's effects on host innate immunity. To test tissue-specific roles of Saa on neutrophil function, we over-expressed saa in the intestine or liver and found that sufficient to partially complement neutrophil phenotypes observed in saa mutants. These results indicate Saa produced by the intestine in response to microbiota serves as a systemic signal to neutrophils to restrict aberrant activation, decreasing inflammatory tone and bacterial killing potential while simultaneously enhancing their ability to migrate to wounds.

SUBMITTER: Murdoch CC

PROVIDER: S-EPMC6405052 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Intestinal Serum amyloid A suppresses systemic neutrophil activation and bactericidal activity in response to microbiota colonization.

Murdoch Caitlin C CC Espenschied Scott T ST Matty Molly A MA Mueller Olaf O Tobin David M DM Rawls John F JF

PLoS pathogens 20190307 3

The intestinal microbiota influences the development and function of myeloid lineages such as neutrophils, but the underlying molecular mechanisms are unresolved. Using gnotobiotic zebrafish, we identified the immune effector Serum amyloid A (Saa) as one of the most highly induced transcripts in digestive tissues following microbiota colonization. Saa is a conserved secreted protein produced in the intestine and liver with described effects on neutrophils in vitro, however its in vivo functions ...[more]

PMID: 30845179

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Project description:The World Health Organization has rated multi-drug resistant (MDR) Pseudomonas aeruginosa as serious threat for human health. It is, however, unclear, whether intestinal MDR P. aeruginosa carriage is associated with inflammatory responses in intestinal or even systemic compartments. In the present study, we generated with respect to their microbiota "humanized" mice by human fecal microbiota transplantation of secondary abiotic mice. Following peroral challenge with a clinical P. aeruginosa isolate on two consecutive days, mice harboring a human or murine microbiota were only partially protected from stable intestinal P. aeruginosa colonization given that up to 78% of mice were P. aeruginosa-positive at day 28 post-infection (p.i.). Irrespective of the host-specificity of the microbiota, P. aeruginosa colonized mice were clinically uncompromised. However, P. aeruginosa colonization resulted in increased intestinal epithelial apoptosis that was accompanied by pronounced proliferative/regenerative cell responses. Furthermore, at day 7 p.i. increased innate immune cell populations such as macrophages and monocytes could be observed in the colon of mice harboring either a human or murine microbiota, whereas this held true at day 28 p.i. for adaptive immune cells such as B lymphocytes in both the small and large intestines of mice with murine microbiota. At day 7 p.i., pro-inflammatory cytokine secretion was enhanced in the colon and mesenteric lymph nodes, whereas the anti-inflammatory cytokine IL-10 was down-regulated in the former at day 28 p.i. Strikingly, cytokine responses upon intestinal P. aeruginosa colonization were not restricted to the intestinal tract, but could also be observed systemically, given that TNF and IFN-? concentrations were elevated in spleens as early as 7 days p.i., whereas splenic IL-10 levels were dampened at day 28 p.i. of mice with human microbiota. In conclusion, mere intestinal carriage of MDR P. aeruginosa by clinically unaffected mice results in pro-inflammatory sequelae not only in intestinal, but also systemic compartments.

Dataset Information

Intestinal Serum amyloid A suppresses systemic neutrophil activation and bactericidal activity in response to microbiota colonization.

Publications

Intestinal Serum amyloid A suppresses systemic neutrophil activation and bactericidal activity in response to microbiota colonization.

Similar Datasets

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