ROS Function in Redox Signaling and Oxidative Stress

Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing Finally, we briefly discuss the characterization of macrophage heterogeneity in humans

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Protective and pathogenic functions of macrophage subsets

Purpose To improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit by developing a risk model that incorporates the gene expression–based “intrinsic” subtypes luminal A, luminal B, HER2-enriched, and basal-like. Methods A 50-gene subtype predictor was developed using microarray and quantitative reverse transcriptase polymerase chain reaction data from 189 prototype samples. Test sets from 761 patients (no systemic therapy) were evaluated for prognosis, and 133 patients were evaluated for prediction of pathologic complete response (pCR) to a taxane and anthracycline regimen. Results The intrinsic subtypes as discrete entities showed prognostic significance (P = 2.26E-12) and remained significant in multivariable analyses that incorporated standard parameters (estrogen receptor status, histologic grade, tumor size, and node status). A prognostic model for node-negative breast cancer was built using intrinsic subtype and clinical information. The C-index estimate for t...

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Supervised Risk Predictor of Breast Cancer Based on Intrinsic Subtypes

Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.

Neutrophil recruitment and function in health and inflammation

From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites

In human breast cancers, a phenotypically distinct minority population of tumorigenic (TG) cancer cells (sometimes referred to as cancer stem cells) drives tumor growth when transplanted into immunodeficient mice. Our objective was to identify a mouse model of breast cancer stem cells that could have relevance to the study of human breast cancer. To do so, we used breast tumors of the mouse mammary tumor virus (MMTV)-Wnt-1 mice. MMTV-Wnt-1 breast tumors were harvested, dissociated into single-cell suspensions, and sorted by flow cytometry on Thy1, CD24, and CD45. Sorted cells were then injected into recipient background FVB/NJ female syngeneic mice. In six of seven tumors examined, Thy1+CD24+ cancer cells, which constituted approximately 1%-4% of tumor cells, were highly enriched for cells capable of regenerating new tumors compared with cells of the tumor that did not fit this profile ("not-Thy1+CD24+"). Resultant tumors had a phenotypic diversity similar to that of the original tumor and behaved in a similar manner when passaged. Microarray analysis comparing Thy1+CD24+ tumor cells to not-Thy1+CD24+ cells identified a list of differentially expressed genes. Orthologs of these differentially expressed genes predicted survival of human breast cancer patients from two different study groups. These studies suggest that there is a cancer stem cell compartment in the MMTV-Wnt-1 murine breast tumor and that there is a clinical utility of this model for the study of cancer stem cells.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2007-0440

Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors.

NLRP6 Protects Il10−/− Mice from Colitis by Limiting Colonization of Akkermansia muciniphila

A growing body of evidence indicates that the gut microbiome plays a role in the development of colorectal cancer (CRC). Patients with CRC harbor gut microbiomes that are structurally distinct from those of healthy individuals; however, without the ability to track individuals during disease progression, it has not been possible to observe changes in the microbiome over the course of tumorigenesis. Mouse models have demonstrated that these changes can further promote colonic tumorigenesis. However, these models have relied upon mouse-adapted bacterial populations and so it remains unclear which human-adapted bacterial populations are responsible for modulating tumorigenesis. We transplanted fecal microbiota from three CRC patients and three healthy individuals into germ-free mice, resulting in six structurally distinct microbial communities. Subjecting these mice to a chemically induced model of CRC resulted in different levels of tumorigenesis between mice. Differences in the number of tumors were strongly associated with the baseline microbiome structure in mice, but not with the cancer status of the human donors. Partitioning of baseline communities into enterotypes by Dirichlet multinomial mixture modeling resulted in three enterotypes that corresponded with tumor burden. The taxa most strongly positively correlated with increased tumor burden were members of the Bacteroides, Parabacteroides, Alistipes, and Akkermansia, all of which are Gram-negative. Members of the Gram-positive Clostridiales, including multiple members of Clostridium Group XIVa, were strongly negatively correlated with tumors. Analysis of the inferred metagenome of each community revealed a negative correlation between tumor count and the potential for butyrate production, and a positive correlation between tumor count and the capacity for host glycan degradation. Despite harboring distinct gut communities, all mice underwent conserved structural changes over the course of the model. The extent of these changes was also correlated with tumor incidence. Our results suggest that the initial structure of the microbiome determines susceptibility to colonic tumorigenesis. There appear to be opposing roles for certain Gram-negative (Bacteroidales and Verrucomicrobia) and Gram-positive (Clostridiales) bacteria in tumor susceptibility. Thus, the impact of community structure is potentially mediated by the balance between protective, butyrate-producing populations and inflammatory, mucin-degrading populations.

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Structure of the gut microbiome following colonization with human feces determines colonic tumor burden

Summary The innate immune system comprises several classes of pattern-recognition receptors, including Toll-like receptors (TLRs) and nucleotide binding and oligomerization domain-like receptors (NLRs). TLRs recognize microbes on the cell surface and in endosomes, whereas NLRs sense microbial molecules in the cytosol. In this review, we focus on the role of NLRs in host defence against bacterial pathogens. Nod1 and Nod2 sense the cytosolic presence of molecules containing meso-diaminopimelic acid and muramyl dipeptide respectively, and drive the activation of mitogen-activated protein kinase and NF-kB. In contrast, Ipaf, Nalp1b and Cryopyrin/Nalp3 promote the assembly of inflammasomes that are required for the activation of caspase-1. Mutation in several NLR members, including NOD2 and Cryopyrin, is associated with the development of inflammatory disorders. Further understanding of NLRs should provide new insights into the mechanisms of host defence and the pathogenesis of inflammatory diseases.

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Intracellular NOD-like receptors in innate immunity, infection and disease.

There is growing evidence that the host innate immune system has a critical role in regulating carcinogenesis, but the specific receptors involved and the importance of their interaction with commensal bacteria need to be elucidated. Two major classes of innate immune receptors, the Toll-like receptors and Nod-like receptors, many of which are upstream of nuclear factor-kappaB, are involved in the detection of intestinal bacteria. The Toll-like receptors have been implicated in promoting colon tumorigenesis, but the role of Nod-like receptors in regulating tumorigenesis remains unclear. Using an established mouse model system of colitis-associated colon tumorigenesis, we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor-related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability. The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice. Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development.

https://cancerres.aacrjournals.org/content/canres/68/24/10060.full.pdf

Grace Y. Chen

Papers

Isolation and molecular characterization of cancer stem cells in MMTV-Wnt-1 murine breast tumors.

NLRP6 Protects Il10−/− Mice from Colitis by Limiting Colonization of Akkermansia muciniphila

Structure of the gut microbiome following colonization with human feces determines colonic tumor burden

Intracellular NOD-like receptors in innate immunity, infection and disease.

The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis