Neutrophil diversity in inflammation and cancer

Neutrophils are the most abundant circulating leukocytes in humans and the first immune cells recruited at the site of inflammation. Classically perceived as short-lived effector cells with limited plasticity and diversity, neutrophils are now recognized as highly heterogenous immune cells, which can adapt to various environmental cues. In addition to playing a central role in the host defence, neutrophils are involved in pathological contexts such as inflammatory diseases and cancer. The prevalence of neutrophils in these conditions is usually associated with detrimental inflammatory responses and poor clinical outcomes. However, a beneficial role for neutrophils is emerging in several pathological contexts, including in cancer. Here we will review the current knowledge of neutrophil biology and heterogeneity in steady state and during inflammation, with a focus on the opposing roles of neutrophils in different pathological contexts

Immune cell networking in solid tumors: focus on macrophages and neutrophils

The tumor microenvironment is composed of tumor cells, stromal cells and leukocytes, including innate and adaptive immune cells, and represents an ecological niche that regulates tumor development and progression. In general, inflammatory cells are considered to contribute to tumor progression through various mechanisms, including the formation of an immunosuppressive microenvironment. Macrophages and neutrophils are important components of the tumor microenvironment and can act as a double-edged sword, promoting or inhibiting the development of the tumor. Targeting of the immune system is emerging as an important therapeutic strategy for cancer patients. However, the efficacy of the various immunotherapies available is still limited. Given the crucial importance of the crosstalk between macrophages and neutrophils and other immune cells in the formation of the anti-tumor immune response, targeting these interactions may represent a promising therapeutic approach against cancer. Here we will review the current knowledge of the role played by macrophages and neutrophils in cancer, focusing on their interaction with other immune cells

Mesenchymal Stromal Cells Do Not Increase the Risk of Viral Reactivation Nor the Severity of Viral Events in Recipients of Allogeneic Stem Cell Transplantation

Mesenchymal stromal cells (MSC) are tested in clinical trials to treat graft versus host disease (GvHD) after stem cell transplantation (SCT). In vitro studies demonstrated MSC's broad immunosuppressive activity. As infections represent a major risk after SCT, it is important to understand the role of MSC in this context. We analyzed 24 patients (pts) receiving MSC for GvHD in our Unit between 2009 and 2011. We recorded viral reactivations as measured in whole blood with polymerase chain reaction for 100 days following MSC administration. In patients with a documented viral reactivation in the first 3 days following MSCs infusion the frequency of virus-specific IFNgamma-producing cells was determined through enzyme-linked immunospot assay. In our cohort of patients viral reactivation after MSC infusion occurred in 45% of the cases, which did not significantly differ from the incidence in a historical cohort of patients affected by steroid resistant GvHD and treated with conventional immunosuppression. No patient presented severe form of infection. Two cases could be checked for immunological response to viral stimulus and demonstrated virus specific T-cytotoxic lymphocyte activity. In our experience MSC infusion did not prove to trigger more frequent or severer viral reactivations in the post transplantation setting

Spatiotemporal expression of endogenous TLR4 ligands leads to inflammation and bone erosion in mouse collagen-induced arthritis

Increased expression of endogenous Toll-like receptor 4 (TLR4) ligands (e.g., Tenascin-C, S100A8/A9, citrullinated fibrinogen (cFb) immune complexes) has been observed in patients with rheumatoid arthritis (RA). However, their roles in RA pathogenesis are not well understood. Here, we investigated the expression kinetics and role of endogenous TLR4 ligands in the murine model of collagen-induced arthritis (CIA). Tenascin-C was upregulated in blood early in CIA, and correlated positively with the clinical score at day 56. Levels of S100A8/A9 increased starting from day 28, peaking at day 42, and correlated positively with joint inflammation. Levels of anti-cFb antibodies increased during the late phase of CIA and correlated positively with both joint inflammation and cartilage damage. Blockade of TLR4 activation at the time of the first TLR4 ligand upregulation prevented clinical and histological signs of arthritis. A TLR4-dependent role was also observed for Tenascin-C and cFb immune complexes in osteoclast differentiation in vitro. Taken together, our data suggests that the pathogenic contribution of TLR4 in promoting joint inflammation and bone erosion during CIA occurs via various TLR4 ligands arising at different stages of disease. The data also suggests that Blockade of TLR4 with monoclonal antibodies is a promising strategy in RA treatment

Doping with artificial oxygen carriers : an update

Potency, selectivity and pharmacokinetics of tofacitinib/CP-690,550 (Janus kinase inhibitor ( JAKi )) and PRT-062607 (spleen tyrosine kinase inhibitor ( SYKi )). a, b Human cell lines were pre-incubated with increasing concentrations of JAKi or SYKi (0.005 to 5 μM) for 1 h and then stimulated with either 100 ng/ml rmIL-6 for 15 minutes or 10 μg/ml anti-IgM for 5 minutes. Cells were fixed, permeabilized, stained with anti-STAT3(pY705)-Alexa Fluor 647 or anti-BLNK(pY84)-Alexa Fluor 488 and quantified by flow cytometry. Half maximal inhibitory concentration (IC 50 ) was extrapolated from an inhibition vs log (concentration) curve. c Collagen-induced arthritis (CIA) model. DBA/1 mice were immunized on day 0 with type II collagen (100 μg/mouse, subcutaneous administration (s.c.)) emulsified in complete Freund’s adjuvant (CFA) and boosted on day 21. Starting on day 30, when disease was mild, mice were orally treated once a day with increasing doses of JAKi (3.75 to 30 mg/kg). Graph shows mean for 6–8 mice/group. d Collagen antibody-induced arthritis (CAIA) model. BALB/c mice received a cocktail of monoclonal antibodies (2 mg, intravenous administration (i.v.)) directed against type II collagen on day 0 and a lipolysaccharide challenge (70 μg, intraperitoneal administration (i.p.)) on day 3. Twice daily treatment with 30 mg/kg SYKi started on day 4. Graph shows mean for 6–8 mice/group. For monitoring both CIA and CAIA models, each paw was scored individually on a scale of 0–4, with 4 indicating the most severe swelling and erythema. e DBA/1 mice received a single oral dose of JAKi (20 mg/kg) or SYKi (30 mg/kg) and plasmatic drug concentration was determined by liquid chromatography-tandem mass spectrometry. Graph shows mean for 2–7 mice/group and a line representing IC50 values obtained in a and b. (PDF 755 kb

Dataset related to article "Neutrophils mediate protection in colitis and carcinogenesis by controlling bacterial invasion and IL-22 production by gdT cells"

<p>This record contains raw data related to article "<strong>Neutrophils mediate protection in colitis and carcinogenesis by controlling bacterial invasion and IL-22 production by gd T cells"</strong></p><p>Abstract</p><p>Neutrophils are the most abundant leukocytes in human blood and play a primary role in resistance against invading microorganisms and in the acute inflammatory response. However, their role in colitis and colitis-associated colorectal cancer is still under debate. Therefore, this study aims to dissect the role of neutrophils in these pathological contexts by using a rigorous genetic approach. Neutrophil-deficient mice (Csf3r-/- mice) were challenged with classic models of colitis and colitis-associated colorectal cancer and the role of neutrophils was assessed by histological, cellular and molecular analyses coupled with adoptive cell transfer and correlative analyses using human datasets. Csf3r-/- mice showed increased susceptibility to colitis and colitis-associated colorectal cancer compared to control Csf3r+/+ mice and adoptive transfer of neutrophils in Csf3r-/- mice reverted the phenotype. In colitis, Csf3r-/- mice showed increased bacterial invasion and reduced number of healing ulcers in the colon, indicating compromised regenerative capacity of epithelial cells. Neutrophils were essential for T cell polarization and IL-22 production. In patients with ulcerative colitis, the expression of CSF3R was positively correlated with IL-22 and IL-23 expression. Moreover, gene signatures associated with epithelial cell development, proliferation and antimicrobial response were enriched in CSF3Rhigh patients. Our data support a model where neutrophils mediate protection against intestinal inflammation and colitis-associated colorectal cancer by controlling the intestinal microbiota and driving the activation of an IL-22-dependent tissue repair pathway.</p><p> </p&gt

Additional file 4: of Fcγ receptor-mediated influx of S100A8/A9-producing neutrophils as inducer of bone erosion during antigen-induced arthritis

NIMPR14- and F4/80-positive cells in the infiltrate and exudate in the joints of FcγRI,II,III−/− mice and their WT controls. Representative photomicrographs of (a) NIMPR14 and (b) F4/80 staining showing neutrophils and macrophages in the infiltrate and exudate of the knee joints of FcγRI,II,III−/− mice and their WT controls at day 7 after induction of antigen-induced arthritis. Original magnification ×400 for infiltrate and ×200 and ×400 for exudate. (PDF 401 kb

Additional file 2: of FcÎł receptor-mediated influx of S100A8/A9-producing neutrophils as inducer of bone erosion during antigen-induced arthritis

Gating strategy for flow cytometric analysis. Gating strategy for flow cytometric analysis used to identify CD11bposLy6Chigh and CD11blow/negLy6Chigh osteoclast precursor populations. First, single cells were selected. For identification of CD11bposLy6Chigh monocytes, cells negative for CD90.2, CD45R/B220, CD49b, NK1.1, and Ly6G and positive for CD11b were selected (gate A). Subsequently, cells were back-gated for side scatter and forward scatter to exclude cells with high granulosity (gate B), and finally Ly6Chigh cells were selected (gate C). For identification of CD11blow/negLy6Chigh, after exclusion of CD90.2-, CD45R/B220-, CD49b-, NK1.1-, Ly6G-positive cells (gate D), cells were gated for their expression of CD11b and Ly6C (CD11Blow/negLy6Chigh) (gate E). (PDF 299 kb

Additional file 3: of Fcγ receptor-mediated influx of S100A8/A9-producing neutrophils as inducer of bone erosion during antigen-induced arthritis

NIMPR14- and F4/80-positive cells in the infiltrate and in the exudate in the joints of FcγRI,II,III,IV−/− mice and their WT controls. Representative photomicrographs of (a) NIMPR14 and (b) F4/80 staining showing neutrophils and macrophages in the infiltrate and exudate of the knee joints of FcγRI,II,III,IV−/− mice and their WT controls at day 7 after induction of antigen-induced arthritis. Original magnification ×400 for infiltrate and ×200 and ×400 for exudate. (PDF 422 kb