Microbiota-Derived Compounds Drive Steady-State Granulopoiesis via MyD88/TICAM Signaling

Abstract

Neutropenia is probably the strongest known predisposition to infection with otherwise harmless environmental or microbiota-derived species. Because initial swarming of neutrophils at the site of infection occurs within minutes, rather than the hours required to induce “emergency granulopoiesis,” the relevance of having high numbers of these cells available at any one time is obvious. We observed that germ-free (GF) animals show delayed clearance of an apathogenic bacterium after systemic challenge. In this article, we show that the size of the bone marrow myeloid cell pool correlates strongly with the complexity of the intestinal microbiota. The effect of colonization can be recapitulated by transferring sterile heat-treated serum from colonized mice into GF wild-type mice. TLR signaling was essential for microbiota-driven myelopoiesis, as microbiota colonization or transferring serum from colonized animals had no effect in GF MyD88−/−TICAM1−/− mice. Amplification of myelopoiesis occurred in the absence of microbiota-specific IgG production. Thus, very low concentrations of microbial Ags and TLR ligands, well below the threshold required for induction of adaptive immunity, sets the bone marrow myeloid cell pool size. Coevolution of mammals with their microbiota has probably led to a reliance on microbiota-derived signals to provide tonic stimulation to the systemic innate immune system and to maintain vigilance to infection. This suggests that microbiota changes observed in dysbiosis, obesity, or antibiotic therapy may affect the cross talk between hematopoiesis and the microbiota, potentially exacerbating inflammatory or infectious states in the host.

The regulation of host defences to infection by the microbiota

“…This suggests that complete immune maturation of the microglia requires a complex microbiota and/or specific bacterial groups within the microbiota. This complements studies of neutrophil production that have also shown that a complex microbiota is a more potent stimulus of neutrophil production than a microbiota of only a limited number of bacterial species 69. Short‐chain fatty acids, which are microbiota‐derived metabolites, were sufficient to restore microglia function in the absence of the microbiota, whereas loss of individual PRRs did not affect microglial activation 74.…”

“…Studies have shown that recognition of bacteria and/or bacterial products from the microbiota by PRRs is the first step in driving this microbiota‐dependent increase in neutrophil production 67, 69. This PRR activation is not restricted to a single site, as PRR ligands in the circulation and at the mucosa are able to drive increased neutrophil production 67, 69. The signals required downstream of PRRs, in contrast, are less well defined.…”

Innate immunity in diabetes and diabetic nephropathy

“…The conflicting results obtained from Myd88 -/-mice may be explained by the complex crosstalk between the microbiota and acute phase emergency granulopoiesis that can occur within minutes of infection 64 . Microbiota-driven myelopoiesis that occurs at concentrations of microbial antigens and PAMPs that are below the threshold required for an adaptive immune response is important for the surveillance of infection 64 .…”

“…Microbiota-driven myelopoiesis that occurs at concentrations of microbial antigens and PAMPs that are below the threshold required for an adaptive immune response is important for the surveillance of infection 64 . The crosstalk between the innate and adaptive immune response, where MyD88 relays the signals of TLR-induced IL1 production, has been shown to be dispensable for TH1 responses in the absence of TREG cells 65 .…”

Do the Microbiota Influence Vaccines and Protective Immunity to Pathogens?

“…In other words, the presence of the microbiota is truly mutualistic, because its chemical directives include separation of the living spaces. These chemical directives also mature the immune system in terms of homeostatic lymphocyte proliferation, increased bone marrow output, and development of secondary lymphoid structures: All of these are establishing conditions for an effective immune response (Kieper et al 2005;Balmer et al 2014).…”