Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions ...of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.
A non-invasive functional-brain-imaging system based on optically-pumped-magnetometers (OPM) is presented. The OPM-based magnetoencephalography (MEG) system features 20 OPM channels conforming to the ...subject's scalp. We have conducted two MEG experiments on three subjects: assessment of somatosensory evoked magnetic field (SEF) and auditory evoked magnetic field (AEF) using our OPM-based MEG system and a commercial MEG system based on superconducting quantum interference devices (SQUIDs). We cross validated the robustness of our system by calculating the distance between the location of the equivalent current dipole (ECD) yielded by our OPM-based MEG system and the ECD location calculated by the commercial SQUID-based MEG system. We achieved sub-centimeter accuracy for both SEF and AEF responses in all three subjects. Due to the proximity (12 mm) of the OPM channels to the scalp, it is anticipated that future OPM-based MEG systems will offer enhanced spatial resolution as they will capture finer spatial features compared to traditional MEG systems employing SQUIDs.
The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. ...Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.
Antineutrophil cytoplasmic antibodies (ANCAs) target proteins normally retained within neutrophils, indicating that cell death is involved in the autoimmunity process. Still, ANCA pathogenesis ...remains obscure. ANCAs activate neutrophils inducing their respiratory burst and a peculiar form of cell death, named NETosis, characterized by formation of neutrophil extracellular traps (NETs), decondensed chromatin threads decorated with cytoplasmic proteins endorsed with antimicrobial activity. NETs have been consistently detected in ANCA-associated small-vessel vasculitis, and this association prompted us to test whether the peculiar structure of NET favors neutrophil proteins uploading into myeloid dendritic cells and the induction of ANCAs and associated autoimmunity. Here we show that myeloid DCs uploaded with and activated by NET components induce ANCA and autoimmunity when injected into naive mice. DC uploading and autoimmunity induction are prevented by NET treatment with DNAse, indicating that NET structural integrity is needed to maintain the antigenicity of cytoplasmic proteins. We found NET intermingling with myeloid dendritic cells also positive for neutrophil myeloperoxidase in myeloperoxidase-ANCA-associated microscopic poliangiitis providing a potential correlative picture in human pathology. These data provide the first demonstration that NET structures are highly immunogenic such to trigger adaptive immune response relevant for autoimmunity.
In this paper, the introduction of nano-sized active fillers into preceramic polymers for the realization of multifunctional ceramic components is discussed. Several silicate and oxynitride systems ...have been produced, by heat treatment in air or nitrogen, greatly widening the compositional range of ceramics made from preceramic polymers. Phase pure ceramics were obtained with very favorable reaction kinetics, and therefore at low temperature and for short heating times. Shaping of the components was carried out using several plastic forming technologies, such as warm pressing, extrusion, injection molding, foaming, machining, fused deposition and 3D printing. Some significant examples of this new methodology are described, ranging from relatively simple oxide systems (mullite, zircon, cordierite, fosterite, yttrium-silicates) to more complex oxynitride ceramics (SiAlONs, YSiONs). Some results concerning the potential application of these components, ranging from structural or thermo-structural functions (bulk components and environmental barrier coatings) to more functional purposes (bioactive ceramics and inorganic phosphors), are also reported.
The family of matricellular proteins comprises molecules with disparate biology. The main characteristic of matricellular proteins is to be expressed during tissue renewal and repair in order to ...“normalize” the tissue. Tumors are wound that do not heal, and tumor growth and metastasis can be viewed as a consequence of aberrant homeostasis, during which matricellular proteins are often upregulated. In the tumor microenvironment, they can be produced by both tumor cells and surrounding stromal cells, such as fibroblasts and macrophages. In this context, matricellular proteins can exert several functions that actively contribute to tumor progression. They may (a) regulate cellular adhesion and migration and extracellular matrix deposition, (b) control tumor infiltration by macrophages or other leukocytes, (c) affect tumor angiogenesis, (d) regulate TGFβ and other growth factor receptor signals, (e) directly stimulate integrin receptors to transduce pro-survival or pro-migratory signals, and (f) regulate the wnt/β-catenin pathways. Most of these functions contribute to settle a chronic low inflammatory state, whose involvement in tissue transformation and tumor progression is now established.
The extracellular matrix (ECM) contributes to the biological and clinical heterogeneity of breast cancer, and different prognostic groups can be identified according to specific ECM signatures. In ...high-grade, but not low-grade, tumors, an ECM signature characterized by high SPARC expression (ECM3) identifies tumors with increased epithelial-to-mesenchymal transition (EMT), reduced treatment response, and poor prognosis. To better understand how this ECM3 signature is contributing to tumorigenesis, we expressed SPARC in isogenic cell lines and found that SPARC overexpression in tumor cells reduces their growth rate and induces EMT. SPARC expression also results in the formation of a highly immunosuppressive microenvironment, composed by infiltrating T regulatory cells, mast cells, and myeloid-derived suppressor cells (MDSCs). The ability of SPARC to induce EMT depended on the localization and suppressive function of myeloid cells, and inhibition of the suppressive function MDSCs by administration of aminobisphosphonates could revert EMT, rendering SPARC-overexpressing tumor cells sensitive to Doxil. We conclude that that SPARC is regulating the interplay between MDSCs and the ECM to drive the induction of EMT in tumor cells.
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•In breast cancer, the extracellular matrix can impact the immune microenvironment•Suppressive activity of myeloid cells is required for EMT of breast cancer cells•Interrupting ECM-MDSCs crosstalk can revert EMT and restore chemosensitivity
Sangaletti et al. show that in high-grade breast cancer, the mesenchymal transition depends on extracellular matrix (ECM)-mediated control of myeloid-derived suppressor cell (MDSC) activity. Interrupting this ECM-MDSC crosstalk with aminobisphosphonates can revert the EMT to restore chemosensitivity.
Cancer-driven granulo-monocytopoiesis stimulates expansion of tumor promoting myeloid populations, mostly myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs). We ...identified subsets of MDSCs and TAMs based on the expression of retinoic-acid-related orphan receptor (RORC1/RORγ) in human and mouse tumor bearers. RORC1 orchestrates myelopoiesis by suppressing negative (Socs3 and Bcl3) and promoting positive (C/EBPβ) regulators of granulopoiesis, as well as the key transcriptional mediators of myeloid progenitor commitment and differentiation to the monocytic/macrophage lineage (IRF8 and PU.1). RORC1 supported tumor-promoting innate immunity by protecting MDSCs from apoptosis, mediating TAM differentiation and M2 polarization, and limiting tumor infiltration by mature neutrophils. Accordingly, ablation of RORC1 in the hematopoietic compartment prevented cancer-driven myelopoiesis, resulting in inhibition of tumor growth and metastasis.
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•RORC1 drives cancer-related myelopoiesis in response to colony-stimulating factors•RORC1+ myeloid cells are a hallmark of tumor-promoting emergency myelopoiesis•RORC1 ablation in the hematopoietic compartment prevents generation of MDSCs and TAMs•RORC1 ablation in the hematopoietic compartment prevents tumor development
Strauss et al. show that RORC1 orchestrates myelopoiesis and supports tumor-promoting innate immunity. Importantly, ablation of RORC1 in the myeloid compartment inhibits tumor growth and metastasis, suggesting a cancer therapeutic approach.
Mast cells are evolutionarily ancient cells, endowed with a unique developmental, phenotypic, and functional plasticity. They are resident cells that participate in tissue homeostasis by constantly ...sampling the microenvironment. As a result of their large repertoire of receptors, they can respond to multiple stimuli and selectively release different types and amounts of mediator. Here, we present and discuss the recent mast cell literature, focusing on studies that demonstrate that mast cells are more than a switch that is turned ‘off’ when in the resting state and ‘on’ when in the degranulating state. We propose a new vision of mast cells in which, by operating in a ‘rheostatic’ manner, these cells finely modulate not only immune responses, but also the pathogenesis of several inflammatory disorders, including infection, autoimmunity, and cancer.
Infection with soil-transmitted helminths (STH) remains a major burden on global health and agriculture. Our understanding of the immunological mechanisms that govern whether an individual is ...resistant or susceptible to infection is derived primarily from model infections in rodents. Typically, experimental infections employ an artificially high, single bolus of parasites that leads to rapid expulsion of the primary infection and robust immunity to subsequent challenges. However, immunity
is generated slowly, and is only partially effective, with individuals in endemic areas retaining low-level infections throughout their lives. Therefore, there is a gap between traditional model STH systems and observations in the field. Here, we review the immune response to traditional model STH infections in the laboratory. We compare these data to studies of natural infection in humans and rodents in endemic areas, highlighting crucial differences between experimental and natural infection. We then detail the literature to date on the use of "trickle" infections to experimentally model the kinetics of natural infection.
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