Transcriptionally and phenotypically dysfunctional neutrophils have a suppressive role in macrophage activation syndrome
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PROVIDER: PRJNA1277345 | ENA |
REPOSITORIES: ENA
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Project description:Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome that complicates rheumatic diseases including systemic juvenile idiopathic arthritis (SJIA). Though neutrophil expansion and activation are key features of SJIA, MAS is associated with neutropenia. As the functional contribution of neutrophils to MAS is largely unexplored, we aimed to define neutrophil dynamics in the TLR9-induced MAS mouse model. Mice with TLR9-MAS showed a transient increase in immature neutrophils during MAS and persistent decrease of mature neutrophils through resolution, even after other MAS features were normalized. Single-cell RNA sequencing confirmed increased proportions of both interferon-stimulated gene-high and immature neutrophils during MAS. We also detected an enhanced interferon signature with upregulation of CD274 (PD-L1), suggesting immunosuppressive roles but distinct form myeloid-derived suppressor cells (MDSC). Furthermore, most of the interferon signature normalized at resolution, but prolonged suppression of IL-1 related genes persisted. Neutrophils from both acute and resolution phases of MAS showed in vitro suppression of pro-inflammatory responses upon LPS stimulation. Notably, antibody mediated neutrophil depletion exaggerated clinical, laboratory, and immunologic features of MAS. Overall, neutrophils in MAS show dynamic changes in subpopulations, including transcriptional and phenotypic dysfunction. These findings suggest that mature neutrophils may play anti-inflammatory roles in MAS and highlights an underappreciated role for neutrophil functions in the pathogenesis of cytokine storm syndromes.
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Project description:Mechanisms regulating transitory suppressive activity of neutrophils in newborns
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Project description:Transitory appearance of immune suppressive polymorphonuclear neutrophils (PMN) defined as myeloid-derived suppressor cells (PMN-MDSC) in newborns is important for their protection from inflammation associated with newly established gut microbiota. Here, we report that inhibition of the type I interferon (IFN1) pathway played a major role in regulation of PMN-MDSC suppressive activity during first weeks of life. Expression of the IFN1 receptor IFNAR1 was markedly lower in PMN-MDSC. However, in newborn mice, down-regulation of IFNAR1 was not sufficient to render PMN immune suppressive. That also required the presence of a positive signal from lactoferrin via its receptor LRP2. The latter effect was mediated via NF-kB activation, which was tempered by IFN1 in a manner that involved SOCS3. Thus, we discovered a mechanism of tight regulation of immune suppressive PMN-MDSC in newborns, which may be used in the development of therapies of neonatal pathologies
2022-05-31 | GSE202264 | GEO
Project description:Polymorphonuclear myeloid derived suppressor cells (PMN-MDSC) are pathologically activated neutrophils that accumulate in cancer and many other pathologic conditions. PMN-MDSC are critically important for the regulation of immune responses in cancer, promotion of tumor progression, and metastases. Despite the recent advances in understanding of the PMN-MDSC biology, the mechanisms responsible for pathological activation of neutrophils are not well defined, which limit selective targeting of PMN-MDSC. Here, we report that mouse and human PMN-MDSC exclusively up-regulate fatty acid transporter protein 2 (FATP2). Over-expression of FATP2 in PMN-MDSC was controlled by GM-CSF, through the activation of STAT5 transcription factor. Genetic ablation of FATP2 abrogated the suppressive activity of PMN-MDSC in spleens and tumors. FATP2 in neutrophils promoted accumulation of oxidized lipids. However, the main mechanism of FATP2 mediated suppressive activity of PMN-MDSC involved uptake of arachidonic acid and synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated activity of PMN-MSC and substantially delayed tumor progression. In combination with check-point inhibitors it blocked tumor progression in mice. Thus, FATP2 mediates acquisition of immune suppressive activity by PMN-MDSC and represents a new target to inhibit the functions of PMN-MDSC and improve the effect of immunotherapy of cancer.
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Project description:We used an ex vivo system of murine ER-Hoxb8 neutrophils that phenotypically and morphologically recapitulate neutrophil maturation stages during five days of in vitro culture in the presence of G-CSF. To investigate the development of the ROS system in neutrophils during their development, we compared transcriptomes of D0, D1, D3 and D5 Hoxb8 neutrophils.
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Project description:Fatty acid transporter 2 regulates lipid metabolism and suppressive function of neutrophils in cancer
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Project description:Myeloid derived suppressor cells (MDSC) playing the immune suppressive roles in tumor bearing host consists of two major subsets of granulocytic and monocytic cells. Granulocytic MDSC (G-MDSC) express CD11b+ Gr-1high Ly6G+ Ly6Clow and produce high level of reactive oxygen species (ROS). Interestingly, neutrophils are well known ROS producing cells during immune defensive process and share same surface markers with G-MDSC. These similar features always brought the fundamental questions what’s the difference between G-MDSC and neutrophils but it’s not yet proven clearly. In this study, we examined the gene expression of G-MDSC and neutrophils using Affymetrix microarray G-MDSC (CD11b+Ly6G+Ly6Clow) were purifed from splenocytes in EL4 lymphoma tumor bearing mice by positive selection of Ly6G using microbeads isolation. Neutrophils were purified from ascitic fluids induced after injection of milk protein, casein by negative selection of F4/80 and positive selection of Ly6G using microbeads isolation. Their RNA was extracted and gene expression was analyzed using Affymetrix microarray.
2011-03-10 | E-GEOD-24102 | biostudies-arrayexpress
Project description:Development of Multiple Myeloma is associated with an accumulation of myeloid derived suppressor cells (MDSCs ) - cells that are morphologically and phenotypically similar to neutrophils (PMN-MDSC) and monocytes (M-MDSC), but are distinct in their functional and biochemical characteristics as well as in their ability to suppress immune responses. In our study, we found that both neutrophils and PMN-MDSCs equally promoted MM survival and decreased MM cell sensitivity to chemotherapy. Therefore, we used a microarray to elucidate the mechanism of the protective effect of neutrophils on myeloma cells.
2018-08-31 | GSE69834 | GEO
Project description:To understand neutrophil impairment in the progression from MGUS through active MM, we investigated the function of mature, high-density neutrophils (HDNs), isolated from peripheral blood. In 7 MM, 3 MGUS and 3 healthy subjects by gene expression profile, we identified a total of 551 upregulated and 343 downregulated genes in MM-HDN, involved in chemokine signaling pathway and FC-gamma receptor mediated phagocytosis conveying in the activation of STAT proteins. In a series of 60 newly diagnosed MM and 30 MGUS patients, by flow-cytometry we found that HDN from MM, and to a lesser extend MGUS, had an up-regulation of the inducible FcγRI (also known as CD64) and a down-regulation of the constitutive FcγRIIIa (also known as CD16) together with a reduced phagocytic activity and oxidative burst, associated to increased immune-suppression that could be reverted by arginase inhibitors in co-culture with lymphocytes. In 43 consecutive newly-diagnosed MM patients, who received first-line treatment based on bortezomib, thalidomide and dexamethasone, high CD64 could identify at diagnosis patients with inferior median overall survival (39.5 versus 86.7 months, p = 0.04). Thus, HDNs are significantly different among healthy, MGUS and MM subjects. In both MGUS and MM neutrophils may play a role in supporting both the increased susceptibility to infection and the immunological dysfunction that leads to tumor progression.
| S-EPMC7005058 | biostudies-literature
Project description:The role of myeloid cells in supporting cancer growth is well established. Most work has focused on myeloid-derived suppressor cells (MDSC) that accumulate in tumor-bearing animals, but tumor-associated neutrophils (TAN) are also known to be capable of augmenting tumor growth. However, little is known about their evolution, phenotype, and relationship to naive neutrophils (NN) and to the granulocytic fraction of MDSC (G-MDSC). In the current study, a transcriptomics approach was used in mice to compare these cell types. Our data show that the three populations of neutrophils are significantly different in their mRNA profiles with NN and G-MDSC being more closely related to each other than to TAN. Structural genes and genes related to cell-cytotoxicity (i.e. respiratory burst) were significantly down-regulated in TAN. In contrast, many immune-related genes and pathways, including genes related to the antigen presenting complex (e.g. all six MHC-II complex genes), and cytokines (e.g. TNF-a, IL-1-a/b), were up-regulated in G-MDSC, and further up-regulated in TAN. Thirteen of the 25 chemokines tested were markedly up-regulated in TAN compared to NN, including striking up-regulation of chemoattractants for T/B-cells, neutrophils and macrophages. This study characterizes different populations of neutrophils related to cancer, pointing out the major differences between TAN and the other neutrophil populations. Various types of myeloid cells have been shown to promote tumor progression by direct immune suppression and by production of angiogenic factors, matrix-degrading enzymes, or growth factors. In untreated tumors, neutrophils have been reported to produce angiogenic factors and matrix-degrading enzymes, support the acquisition of a metastatic phenotype, and suppress the anti-tumor immune response. Neutrophils, like all other leukocytes, move into tissues from the blood under the influence of specific chemokines (e.g. KC/CXCL-1, MIP-2a/CXCL-2 and GCP-2/CXCL-6), cytokines (e.g. TNFa and IFN-x), and cell adhesion molecules located on their own surface (e.g. CD11b) and on the surface of endothelial cells (e.g. selectins, ICAM-1 and PECAM-1). When they traffic into tumors, they are referred to as TAN. In mice, TAN can be defined by the specific surface markers CD11b and Ly6G with low expression of macrophage markers such as F4/80. Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immune suppressive cells that are produced excessively in cancer. They comprise at least two subsets -granulocytic (Ly6G+, G-MDSC) and monocytic cells (Ly6C+, M-MDSC), potentially with different immunosuppressive properties. It has been previously shown that MDSC can enter tumors and differentiate to mature macrophages (TAM) or neutrophils (TAN). However, since no definitive markers have been established, it is unknown whether intratumoral N2 neutrophils (N2 TAN) are granulocytic MDSC from spleen that are attracted to the tumor or if they are typical blood-derived neutrophils that are then converted to an N2 phenotype by the tumor microenvironment, specifically by the high local concentrations of TGF-b. The purpose of this study was to use a transcriptomics approach to gain further information about TANs by comparing the RNA profile of these cells to naive bone-marrow neutrophils (NN) and to the granulocytic fraction of myeloid derived suppressor cells (G-MDSC). We examined which pathways and gene-groups varied amongst these 3 populations of neutrophils and performed a detailed analysis on pathways related to the main functions of neutrophils, such as respiratory burst, granule proteins, phagocytosis, apoptosis, structural genes, antigen presentation and specific immune effects. Our data defines TAN as a unique population of neutrophils, quite distinct from both NN and G-MDSC.
2013-01-04 | E-GEOD-43254 | biostudies-arrayexpress