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.

The Role of the Bone Marrow Stromal Compartment in the Hematopoietic Response to Microbial Infections

“…During polibacterial sepsis, osteoblast (Ob) numbers are decreased through the activation of apoptotic programs mediated by G-CSF (75). Administration of the bacterial second messenger c-di-GMP leads to reduced numbers of CXCL12-abundant reticular cells (CARc) and SECs (80). (C) Myeloid cells, mainly macrophages and aged neutrophils, modulate CXCL12 production by CAR cells, leading to the cyclic release of hematopoietic stem cells (HSCs) from BM to circulation (91, 92).…”

“…For instance, administration of the bacterial second messenger bis-(3′–5′)-cyclic dimeric guanosine (c-di-GMP) was recently shown to strongly reduce endothelial and CAR cell numbers in BM and compromise their ability to produce relevant HSPC niche factors, such as CXCL12 or kit-L (80). Consequently, HSPCs were mobilized to the periphery, subsequently homing and proliferating in the spleen.…”

Developmental HSC Microenvironments: Lessons from Zebrafish

“…Adult HSCs can proliferate in response to inflammatory cues from systemic infection or myeloablation and differentiate to replace lost effector immune cells (Baldridge et al 2010; Essers et al 2009; Feng et al 2008; Kobayashi et al 2015; Takizawa et al 2011, 2012). This response of HSCs is not a secondary outcome to the loss of immune cells, but rather a direct response to inflammatory cytokines (Baldridge et al 2010; Essers et al 2009).…”

An RNA-Based Fluorescent Biosensor for High-Throughput Analysis of the cGAS-cGAMP-STING Pathway

“…While current efforts have focused on targeting STING with natural and unnatural cyclic dinucleotides and the small molecule DMXAA (Baird et al, 2016; Chandra et al, 2014; Corrales et al, 2015; Demaria et al, 2015; Deng et al, 2014; Downey et al, 2014; Kobayashi et al, 2015; Nakamura et al, 2015; Zhang et al, 2015), cGAS may be an advantageous drug target because activating the enzyme can produce an amplified signal relative to the STING receptor-small molecule interaction. cGAS also may be an attractive target for small molecule inhibition in the case of autoimmune diseases.…”