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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

tumor microenvironment --- monocyte --- macrophage --- neutrophil --- immunosuppression --- immunotherapy

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This eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contact

Medicine --- Immunology --- tumor microenvironment --- monocyte --- macrophage --- neutrophil --- immunosuppression --- immunotherapy --- tumor microenvironment --- monocyte --- macrophage --- neutrophil --- immunosuppression --- immunotherapy

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Ginsenoside Rh2 is a tritepenic saponin naturally produced by ginseng (Nag and al., 2012). This molecule could be an inhibitor of cell proliferation for many cancer cell lines (Chung and al., 2013; Kil and al., 2004; Nakata and al., 1998; Popovich and Kitts, 2002, 2004) and moreover, an inhibitor of the Multidrug Resistance Protein (Jin, Shahi, Kang, van Veen & Fan, 2006); Zhang and al. 2010). This ginsenoside would also have anticancerous properties that caught our interest (K. Choi & Choi, 2009; Guo and al., 2012; Park and al; 2012; Park and al., 2010; Yi and al., 2009). Many studies described different modes of action for ginsenoside Rh2 Yi and al. suggested that the ginsenoside triggered apoptsosis via Rh2-dependent disorganization of cholesterol-enriched microdomains (rafts). This alteration would be associated with the apoptosis via the extrinsic way. Parallel with studies aimed to characterize the interaction between cholesterol and ginsenoside Rh2 together with the consequences of this interaction on biophysical membrane properties, we tried as part of this work to confirm or invalidate the role of cholesterol in the mechanism of action of ginsenoside Rh2.To do this, we first characterized ginsenoside Rh2-induced necrosis and RH2-induced apoptosis on two cell lines: THP-1 and U937. Next, following the caspase 8 activity, we measured the apoptosis activation via the extrinsic way in the presence of ginsenoside Rh2. Finally, we invested the role of cholesterol in the ginsenoside Rh2-induced cytotoxicity from 24 hours of incubation and 40µM.Whatever the cell line, the apoptosis seems to precede the necrosis. We did not measure any significant increase of caspase 8 activity, or any effects of the caspase 8’s inhibitor on the ginsenoside-induced cytotoxicity. We concluded the extrinsic way of apoptosis was not activated by the ginsenoside Rh2 on the THP-1 and U937 cell lines. Eventually, variations of the cholesterol content seem to be important to Rh2-induced cytotoxicity. We suggested a potential involvement of cholesterol contents in the mode of action of the ginsenoside Rh2. Cholesterol depleted cells are more sensitive to Rh2-induced apoptosis so after 2 hours of incubation, cytotoxicity is already strongly increased compared to the control condition. Comparatively, the cholesterol-overloaded cells are less sensitive to Rh2-induced apoptosis so in these overloaded-cells apoptosis seems to be delayed from 24 hours of incubation.At the end of this work, cholesterol appears as a key element of the apoptotic cytotoxicity induced by ginsenoside Rh2. By this way, molecules able to alter the cholesterol-enriched microdomains (rafts) could be interesting compounds in a pharmacological point of view. Le ginsénoside Rh2 est une saponine de type triterpénique naturellement produite par le ginseng (Nag et al., 2012). Cette molécule aurait un effet inhibiteur sur la prolifération cellulaire de nombreuses lignées cancéreuses (Chung et al., 2013; Kim et al., 2004; Nakata et al., 1998; Popovich & Kitts, 2002, 2004} ainsi que sur les M ultidrug Resistance Protein (Jin, Shahi, Kong, van Veen, & Fan, 2006; Zhang et al., 2010). Le gmsénoside Rh2 présenterait également des prop riétés anti-cancéreuses intrinsèques auxquelles nous nous sommes intéressés (K. Choi & Choi, 2009; Guo et al., 2012; Park et al., 2010; Yiet al., 2009). Parmiles études décrivant les voies moléculaires impliquées dans le mode d'action du ginsénoside Rh2, Yi and off suggèrent que l'apoptose en présence de ginsénoside est déclenchée par une désorganisation Rh2 -dépendante des micradomaines membranaires enrichis en cholestérol (rafts), qui serait responsable d'une activation de la voie extrinsèque de l'apoptose.En parallèle à des études visant à caractériser l'interaction du ginsénoside Rh2 avec le cholestérol et les conséquences de cette interaction sur les propriétés biophysiques des membranes, nous avons cherché, dans le cadre de ce mémoire, à confirmer ou à infirmer l'hypothèse impliquant les rafts dans le mécanisme d'action du Rh2. Pour ce faire, nous avons d'abord caractérisé la nécrose et l'apoptose induites par le ginsénoside Rh2 sur 2 lignées cellulaires : les cellules THP-1 et U937. En suivant l'activité de la caspase 8, nous avons ensuite mesuré l' activation de la voie extrinsèque de lapoptose en présence de ginsénoside Rh2. Enfin, nous avons évalué l'implication du cholestérol dans la cytotoxicité induite par le ginsénoside. La nécrose et l'apoptose induites pa r le ginsénoside Rh2 sont caractérisées par une cytotoxicité temps et concentrations-dé pendantes dès 24h d 'incubation à part ir d'une concentration de 40µM. Quelle que soit la lignée cellulaire, l'apoptose semble précéder la nécrose. Nous n'avons pas observé d 'augmentation significative de lactivité de la caspase 8 en présence de ginsénoside Rh2 sur les lignées cellulaires THP-1 et U937, ni d'effet de l'inhibiteur de cette caspase sur la cytotoxicité induite par le ginsénoside, suggérant que Io voie extrinsèque de lapoptose n'est pas impliquée. Finalement, nous avons montré un impact du contenu en cholestérol sur la cytotoxicité associée au Rh2 ce qui suggère une implication po tentielle du cholestérol dons le mode d'action du ginsénoside. Lorsque l'on déplète les cellules en cholestérol, l'apoptose induite par le ginsénoside Rh2 est fortement augmentée dès 2h d 'incubation. Lorsqu'on surcharge les cellules en cholestérol, par contre, l'apoptose semble être retardée, voire diminuée à partir de 24h d 'incubation.Au terme de ce travail, le cholestérol apparait comme un élément clef de la cytotoxicité apoptotique induite por le ginsénoside Rh2, faisant des molécules susceptibles de modifier les domaines enrichis en cholestérol (rafts), des composés potent iellement intéressants d'un point de vue pharmacologique.

ginsenoside Rh2 --- Ginsenosides --- macrophage-derived immunosuppressor factor --- U937 Cells --- Neoplasms

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Activation of innate immune system underlies both pathological and physiological inflammatory responses and is critical for the host. Regulated innate immune response is thus essential not only for the elimination of invading pathogens but also for the restoration of tissue homeostasis. The innate immune system relies on the expression of families of highly conserved Pattern Recognition Receptors (PRRs) by specialised immune cells such as macrophages or dendritic cells. Engagement of PRRs by microbial or host-derived danger signals coordinates the cellular innate immune response. While some receptors such as Toll-like Receptors (TLRs) and C-type Lectin Receptors (CLRs) are membrane bound, others like the Retinoic-acid-Inducible Gene I (RIG-I)-Like Receptors (RLRs), Nucleotide-binding Oligomerization Domain (NOD)-Like Receptors (NLRs) and several DNA receptors (e.g. AIM2, cGAS) are expressed in the cytosol. Moreover, several molecules released by innate immune cells including complement proteins and members of the pentraxin family act as soluble PRRs. Activation of PRRs initiate specific signal transduction cascades, which lead to transcription and secretion of inflammatory mediators, thereby facilitating inflammation. Furthermore, some PRRs can form large oligomeric protein complexes called inflammasomes that instigate proteolytic maturation of members of the IL-1 family of cytokines, thereby driving inflammatory programmed cell death. Current research on immunomodulation is focused on understanding the fundamental mechanisms that control the activation and regulation of innate immune cell function. This includes exciting advances in understanding signals that can polarize innate immune cells into different functional states, for instance from a more inflammatory to a more tolerogenic profile. However, this response of innate immune cells critically depends on several intrinsic and extrinsic factors such as their own biological status and their microenvironmental context, respectively. For instance, it is known that the extracellular matrix or biomaterials can modulate macrophage behavior and that autophagy flux is a critical regulator of inflammation. Consistent with this, there has been an increase in the development of novel drugs and biomaterials aimed at inducing immunomodulatory responses in targeted innate immune cell populations to be used in the context of tissue regeneration, cancer, autoimmune disease etc. Thus, a thorough understanding of immunomodulatory mechanisms of innate immune cells will guide the development of novel therapeutic strategies aimed to control inflammation-mediated pathologies. In this Research Topic, we aim to highlight recent advances in our understanding of the fundamental mechanisms controlling activation of innate immune cells and document new strategies to study and manipulate their immunomodulation.

Medicine --- Immunology --- innate immunity --- PRRs --- immunomodulation --- pattern recognition --- macrophage polarization

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Historically the study of the immune system and metabolism have been two very separate fields. In recent years, a growing literature has emerged illustrating how the multiple processes of cellular metabolism are intricately linked to several aspects of immune function and development. This Research Topic covers recent progress in the field now known as “Immunometabolism” and the role of metabolism in immune tolerance. Immune tolerance is operationally defined as a state where a host’s immune system is balanced such that although self-reactive lymphocytes are present, they are kept in check by immune regulation. Perturbations to this homeostasis may result in self-reactive lymphocytes gaining the upper hand and mediating auto-immune disease. Maintenance of immune tolerance involves a large cast of different cell types including effector T cells, regulatory T cells, B cells, stromal cells, dendritic cells and macrophages. Intracellular pathways and individual enzymes of metabolism have been shown to be harnessed by cells of both the adaptive and innate immune system to allow particular immune functions to be achieved. Examples include metabolic enzymes serving ‘moonlighting’ functions in mRNA translation, gene splicing, and kinase activation. Other examples include the requirement for de novo fatty acid synthesis for differentiation into Th17 effectors and CD8 memory T cells or products of the TCA cycle promoting pro-inflammatory cytokine production. Likewise, the availability of extracellular metabolic substrates has a large impact on the maintenance of local immune tolerance. For example, there are different requirements for glucose, glutamine and fatty acids for effector versus regulatory T cell development. Also tolerogenic dendritic cells mediate lowering of extracellular essential amino acids by their enhanced catabolism, promoting the induction of regulatory T cells. The purpose of this Research Topic is to provide an update on the current understanding of the multiple roles for metabolism in regulating the immune system.

B cell --- T cell --- Immune Tolerance --- macrophage --- GvHD --- Transplantation --- Metabolism