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Review
. 2016 Nov;100(5):865-879.
doi: 10.1189/jlb.3RI0516-222R. Epub 2016 Sep 7.

Microbiota-myeloid cell crosstalk beyond the gut

Sayeh Gorjifard  1 , Romina S Goldszmid  2
Affiliations
Review

Microbiota-myeloid cell crosstalk beyond the gut

Sayeh Gorjifard et al. J Leukoc Biol. 2016 Nov.

Abstract

The gut microbiota is a complex and dynamic microbial ecosystem that plays a fundamental role in host physiology. Locally, the gut commensal microbes/host symbiotic relationship is vital for barrier fortification, nutrient absorption, resistance against intestinal pathogens, and the development and maintenance of the mucosal immune system. It is now clear that the effects of the indigenous intestinal flora extend beyond the gut, ranging from shaping systemic immune responses to metabolic and behavioral functions. However, the underlying mechanisms of the gut microbiota/systemic immune system interactions remain largely unknown. Myeloid cells respond to microbial signals, including those derived from commensals, and initiate innate and adaptive immune responses. In this review, we focus on the impact of the gut microbiota on myeloid cells at extraintestinal sites. In particular, we discuss how commensal-derived signals affect steady-state myelopoiesis and cellular function and how that influences the response to infection and cancer therapy.

Keywords: cancer; host–microbial interactions; infection; mononuclear phagocytes; systemic immunity.

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Figures

Figure 1
Figure 1
Microbiota regulation of steady‐state myelopoiesis and neutrophil homeostasis. HSPCs and myeloid progenitors express PRRs that enable them to sense bacteria‐derived products directly. Commensal‐derived signals modulate myelopoiesis, mostly by affecting GMP frequencies and differentiation potential. The gut microbiota promotes granulopoiesis, at least in part, through the local induction of IL‐17 production and increased plasma levels of G‐CSF. The absence of gut commensal microbiota leads to reduced numbers and differentiation potential of GMPs, leading to reduced neutrophil, monocyte, and macrophage numbers in the BM and peripheral tissues. Bacterial metabolites, such as SCFAs, modulate DC differentiation by increasing the numbers of CDPs. Commensal microbes also regulate neutrophil function in the BM through direct recognition of microbial‐derived peptidoglycan via the Nod1 receptor. Circulating neutrophil aging is driven by microbiota‐derived signals via TLR/MyD88 signaling, and absence of commensals leads to reduced numbers of CXCR4hi/L‐Selectinlow‐aged neutrophils in circulation.
Figure 2
Figure 2
Microbiota modulation of myeloid cell function at extraintestinal sites: impact on response to invading pathogens. The preconditioning of neutrophils by microbiota‐derived signals is required for their extravasation from the bloodstream into the inflamed tissue and for their optimal production of ROS and RNS and bactericidal activity. The microbiota provides tonic signals needed for macrophage bacterial killing capacity. Gut commensal microbes also calibrate macrophage and DC responsiveness to viral infections through chromatin remodeling of antiviral genes that constitutively express histone marks of transcriptionally activated genes (H3K4me3). IL‐12, produced by the microbiota‐calibrated DCs, leads to NK cell activation. Migratory and antigen‐presenting capabilities of lung DCs are modulated by the microbiota as well. In the absence of commensal microbes, there is a reduced influx of neutrophils, macrophages, and DCs to sites of inflammation and infection, and the cells display impaired functions, leading to delayed pathogen clearance.
Figure 3
Figure 3
Commensal intestinal microbes modulate the response to various cancer therapies and promote spontaneous anti‐tumor immunity. (1–3) Therapies that cause damage to the intestinal epithelial barrier allow for changes in microbial composition and/or bacterial translocation and benefit from the adjuvant effect of commensal microbes. (1) Anti‐CTLA‐4 treatment leads to intraepithelial cell (IEC) apoptosis and disrupts the microbiota–host equilibrium, leading to enrichment in Bacteroides spp., which in turn, activate DCs for IL‐12 production and priming of anti‐bacteria CD4+ T cells that contribute to therapy efficacy. IEL, Intraepithelial lymphocyte; MHC‐II, MHC class II. (2) CTX induces mucositis, followed by dysbiosis and translocation of Gram‐positive bacteria that promote the induction of pTh17 and Th1 memory cells. (3) Total body irradiation (TBI), a preconditioning regime used before adoptive T cell transfer therapy, leads to mucosal barrier disruption and translocation of bacteria and bacterial products that lead to DC activation and promote the transferred cell anti‐tumor activity. (4–6) Microbiota‐derived signals prime myeloid cells for effective response to therapy. (4) Members of the Bifidobacterium genus constitutively present in the gut microbiota activate DCs, resulting in enhanced, spontaneous anti‐tumor CD8+ T cell responses. The increased frequencies of anti‐tumor CD8+ T cells in mice harboring Bifidobacterium spp. facilitate the response to anti‐PD‐L1 treatment. (5) Signals from the microbiota and in particular, Alistipes shaii and Ruminococcus spp. enable tumor‐infiltrating myeloid cells to respond to CpG‐ODN following TLR9 ligation and to produce proinflammatory cytokines (e.g., TNF, IL‐12). The CpG‐ODN activity, in combination with IL‐10R blockade (anti‐IL‐10R), leads to hemorrhagic necrosis and priming of Th1 and CTL anti‐tumor responses needed for therapy efficacy. (6) Microbiota tonic signaling conditions tumor‐infiltrating myeloid cells to produce ROS in response to oxaliplatin. ROS production by myeloid cells is required for oxaliplatin‐induced DNA damage, thus contributing to the early genotoxic effect of the drug.
Figure 4
Figure 4
The gut microbiota modulates the response to systemic infection and cancer therapy via the regulation of myeloid cell development and function. The gut microbiota regulates myelopoiesis in the BM and at extramedullary sites (liver and spleen). Both infection and cancer induce dysregulated myelopoiesis. Factors produced at the inflamed sites trigger the mobilization, proliferation, and differentiation of HSCs and the recruitment of neutrophils and inflammatory monocytes to the infected tissues and tumor microenvironment. At the site of infection, inflammatory monocytes differentiate into inflammatory DCs and macrophages that promote Th1 responses and pathogen eradication. On the other hand, in the suppressive tumor microenvironment, these cells favor tumor growth. Following chemo‐ and immunotherapy, myeloid cells can become proinflammatory and lead to tumor destruction, whereas at the site of infection, immunosuppressive myeloid cell function contributes to resolution of inflammation. Microbiota tonic signaling allows for the proper differentiation and function of myeloid cells, facilitating pathogen killing and resolution of inflammation to avoid collateral damage to self, and the efficient response to cancer therapy.
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