Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis

Hergott, Christopher B.; Roche, Aoife M.; Tamashiro, Edwin; Clarke, Tom; Bailey, Aubrey; Laughlin, Alice; Bushman, Frederic D.; Weiser, Jeffrey N.

doi:10.1182/blood-2015-10-675173

Cited by 98 publications

(79 citation statements)

References 72 publications

(86 reference statements)

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“…While tumor‐derived factors and the tumor microenvironment can reprogram marrow to drive granulopoiesis and generation of neutrophils with distinct phenotypes, other factors may also do so. For example, recent studies point to the microbiome influencing neutrophil lifespan and function, including the propensity to generate NETs . The influence of the microbiome on neutrophil biology may be of particular relevance in patients with cancer where microbiome alterations can result from several factors, including mucosal injury from chemotherapy and radiation and the widespread use of antibiotics.…”

Section: Future Therapeutic Strategies Targeting Neutrophils In the Tmentioning

confidence: 99%

Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

Singel

Segal

2016

Immunological Reviews

156

130

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Summary Neutrophils are the first responders to infection and injury and are critical for antimicrobial host defense. Through the generation of reactive oxidants, activation of granular constituents and neutrophil extracellular traps, neutrophils target microbes and prevent their dissemination. While these pathways are beneficial in the context of trauma and infection, their off-target effects in the context of tumor are variable. Tumor-derived factors have been shown to reprogram the marrow, skewing toward the expansion of myelopoiesis. This can result in stimulation of both neutrophilic leukocytosis and the release of immature granulocytic populations that accumulate in circulation and in the tumor microenvironment. While activated neutrophils have been shown to kill tumor cells, there is growing evidence for neutrophil activation driving tumor progression and metastasis through a number of pathways, including stimulation of thrombosis and angiogenesis, stromal remodeling, and impairment of T cell-dependent anti-tumor immunity. There is also growing appreciation of neutrophil heterogeneity in cancer, with distinct neutrophil populations promoting cancer control or progression. In addition to the effects of tumor on neutrophil responses, anti-neoplastic treatment, including surgery, chemotherapy, and growth factors, can influence neutrophil responses. Future directions for research are expected to result in more mechanistic knowledge of neutrophil biology in the tumor microenvironment that may be exploited as prognostic biomarkers and therapeutic targets.

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Section: Future Therapeutic Strategies Targeting Neutrophils In the Tmentioning

confidence: 99%

Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

Singel

Segal

2016

Immunological Reviews

156

130

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“…The resulting agglomeration of immune cells and structures helps to manage and contain the microbiota at the mucosa 23, 24. The microbiota also drives the maturation of systemic immunity beyond the confines of the mucosa, including in major immune tissues such as the bone marrow and spleen 25, 26, 27, 28, 29, 30. The importance of host–microbiota interactions for our health has been highlighted by clinical studies and work with animal models demonstrating that microbiota dysbiosis is associated with diseases and immune dysfunctions in both intestinal and extra‐intestinal tissues.…”

Section: Introductionmentioning

confidence: 99%

The regulation of host defences to infection by the microbiota

Brown

Clarke

2016

Immunology

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SummaryThe skin and mucosal epithelia of humans and other mammals are permanently colonized by large microbial communities (the microbiota). Due to this life‐long association with the microbiota, these microbes have an extensive influence over the physiology of their host organism. It is now becoming apparent that nearly all tissues and organ systems, whether in direct contact with the microbiota or in deeper host sites, are under microbial influence. The immune system is perhaps the most profoundly affected, with the microbiota programming both its innate and adaptive arms. The regulation of immunity by the microbiota helps to protect the host against intestinal and extra‐intestinal infection by many classes of pathogen. In this review, we will discuss the experimental evidence supporting a role for the microbiota in regulating host defences to extra‐intestinal infection, draw together common mechanistic themes, including the central role of pattern recognition receptors, and outline outstanding questions that need to be answered.

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“…Previous work in mice has demonstrated that PGN derived from gut microbiota can influence remote tissues and organs [31,32] . In flies, gut Ecc release PGN that can cross the gut epithelium and its surrounding muscles and reach the hemolymph where it activates the NF-κB pathway in FB cells [33] .…”

Section: Drosophila Slc15 Transporters Are Not Required For Pgn Transmentioning

confidence: 99%

Oligopeptide Transporters of the SLC15 Family Are Dispensable for Peptidoglycan Sensing and Transport in <b><i>Drosophila</i></b>

et al. 2017

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Peptidoglycan (PGN) detection by PGN recognition proteins (PGRP) is the main trigger of the antibacterial immune response in Drosophila. Depending on the type of immune cell, PGN can be sensed either at the cell membrane by PGRP-LC or inside the cell by PGRP-LE, which plays a role similar to that of Nod2 in mammals. Previous work, mainly in cell cultures, has shown that oligopeptide transporters of the SLC15 family are essential for the delivery of PGN for Nod2 detection inside of the cells, and that this function might be conserved in flies. By generating and analyzing the immune phenotypes of loss-of-function mutations in 3 SLC15 Drosophila family members, we tested their role in mediating PGRP-LE-dependent PGN activation. Our results show that Yin, CG2930, and CG9444 are required neither for PGRP-LE activation by PGN nor for PGN transport from the gut lumen to the insect blood. These data show that, while intracellular PGN detection is an essential step of the antibacterial response in both insects and mammals, the types of PGN transporters and sensors are different in these animals.

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Peptidoglycan from the gut microbiota governs the lifespan of circulating phagocytes at homeostasis

Abstract: Key Points The intestinal microbiota regulates the steady-state survival and turnover kinetics of circulating neutrophils and inflammatory monocytes. The cytoplasmic peptido-glycan sensor Nod1 relays microbial signals into IL-17A–dependent stimulation of myeloid cell persistence.

Cited by 98 publications

References 72 publications

Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

The regulation of host defences to infection by the microbiota

Oligopeptide Transporters of the SLC15 Family Are Dispensable for Peptidoglycan Sensing and Transport in <b><i>Drosophila</i></b>

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