Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING.

Abstract

Upon systemic bacterial infection, hematopoietic stem and progenitor cells (HSPCs) migrate to the periphery in order to supply a sufficient number of immune cells. Although pathogen-associated molecular patterns reportedly mediate HSPC activation, how HSPCs detect pathogen invasion in vivo remains elusive. Bacteria use the second messenger bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP) for a variety of activities. Here, we report that c-di-GMP comprehensively regulated both HSPCs and their niche cells through an innate immune sensor, STING, thereby inducing entry into the cell cycle and mobilization of HSPCs while decreasing the number and repopulation capacity of long-term hematopoietic stem cells. Furthermore, we show that type I interferon acted as a downstream target of c-di-GMP to inhibit HSPC expansion in the spleen, while transforming growth factor-β was required for c-di-GMP-dependent splenic HSPC expansion. Our results define machinery underlying the dynamic regulation of HSPCs and their niches during bacterial infection through c-di-GMP/STING signaling.

• Authors: Hiroshi Kobayashi, Chiharu I Kobayashi, Ayako Nakamura-Ishizu, Daiki Karigane, Hiroshi Haeno, Kimiyo N Yamamoto, Taku Sato, Toshiaki Ohteki, Yoshihiro Hayakawa, Glen N Barber, Mineo Kurokawa, Toshio Suda, Keiyo Takubo
• Journal: Cell reports (Cell Rep) Vol. 11 Issue 1 Pg. 71-84 (Apr 07 2015) ISSN: 2211-1247 [Electronic] United States
• PMID: 25843711 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Interferon Regulatory Factor-3
• Irf3 protein, mouse
• Membrane Proteins
• Sting1 protein, mouse
• Transforming Growth Factor beta
• bis(3',5')-cyclic diguanylic acid
• Cyclic GMP

Topics

• Animals
• Bacteria (metabolism, pathogenicity)
• Cyclic GMP (administration & dosage, analogs & derivatives, immunology, metabolism)
• Gene Expression Regulation
• Hematopoietic Stem Cells (immunology, metabolism, microbiology)
• Immunity, Innate
• Interferon Regulatory Factor-3 (genetics, immunology)
• Membrane Proteins (genetics, immunology)
• Mice
• Signal Transduction (drug effects, immunology)
• Stem Cell Niche (immunology)
• Transforming Growth Factor beta (genetics, immunology)