RT Journal Article
SR Electronic
T1 Intestinal Serum Amyloid A suppresses systemic neutrophil activation and bactericidal activity in response to microbiota colonization
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 435503
DO 10.1101/435503
A1 Caitlin C. Murdoch
A1 Scott T. Espenschied
A1 Molly A. Matty
A1 Olaf Mueller
A1 David M. Tobin
A1 John F. Rawls
YR 2018
UL http://biorxiv.org/content/early/2018/10/04/435503.abstract
AB The intestinal microbiota influence diverse aspects of host physiology, including the development and function of myeloid lineages. Numerous host and microbial factors are known to poise neutrophils and other granulocytes for response to pathogens and danger signals, yet the mechanisms by which the intestinal microbiota regulate this process are largely unknown. 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 are 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 mRNAs and bactericidal activity. Saa’s effects on neutrophils depends on microbiota colonization, suggesting this protein mediates the microbiota’s influence on host innate immunity. To test tissue-specific roles of Saa on neutrophil function, we generated transgenic zebrafish over-expressing saa in the intestine. Transgenic intestinal saa expression was sufficient to partially complement the neutrophil phenotypes 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.