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Angiogenesis, the sprouting of new blood vessels from existing ones, is a process important both in physiological and pathogenic conditions. During angiogenesis, endothelial cells proliferate, migrate and organize into new, functional blood vessels. Macrophages play an important role in this process as they process microenvironmental cues, and directly secrete or stimulate other cell types to secrete pro-angiogenic mediators, including chemokines, cytokines and growth factors that together stimulate endothelial cell proliferation, degrade the extracellular matrix (ECM), and attract leukocytes to further enhance angiogenesis. Since macrophages are extremely plastic and can be differently activated by various stimuli, they exert many regulatory effects on angiogenesis, although many aspects of this regulation are still unclear. This volume highlights several examples of macrophages-driven regulation of angiogenesis. We begin with an introductory review which describes the role of tumor-associated macrophages (TAMs) in angiogenesis and lymphangiogenesis. Riabov et al. (2014) describe the crosstalk between tumor cells and TAMs in hypoxic and cytokine-rich microenvironment, resulting in the induction of pro-angiogenic behavior in both cell types. We then chose to highlight the role of the chitinases, a family of proteins with newly discovered roles in angiogenesis. In this review by Shao (2013), the roles and mode of action of YKL-40/chitinase-3-like-1 (CHI3L1) are described focusing on its angiogenic signature pertaining to tumor vascularization and development. YKL-40 regulates tumor vascularization mediated by endothelial cells and promotes vascular integrity supported by smooth muscle cells. Shao also reports that while YKL-40-induced angiogenic response in endothelial cell is VEGF-independent, YKL-40 itself is induced when VEGF is inhibited. Next, an original paper by Libreros et al. (2013) suggests that increased levels of CHI3L1 produced by pulmonary macrophages set up the pre-metastatic niche in breast cancer. CHI3L1 enhances angiogenesis by inducing chemokines (CCL2 and CXCL2) and MMP-9 expression, and attraction of macrophages into the lung. The importance of CHI3L1 as a regulator of angiogenesis, as well as possible target of treatment, is demonstrated by the addition of chitin microparticles that can inhibit CHI3L1, chemokines and MMP-9 production in the pre-metastatic lung. Several pro-inflammatory mediators are long known to be involved in angiogenesis, and the next three reviews elaborate on these. Owen and Mohamadzadeh (2013) describe the potential roles of M2 TAMs in modulating angiogenesis through production of chemokines. The role of the pro-angiogenic ELR+ chemokines that attract neutrophils, and the angiostatic ELR-chemokines, with the exception of CXCL12, are discussed in the context of tumor progression. M1 vs. M2 secreted profiles of cytokines/chemokines which may play roles in immune regulation, angiogenesis, tumor progression and metastasis are highlighted. Voronov et al. (2014) describe the roles of the IL-1 family of proteins in angiogenesis, and especially IL-1β that can directly drive endothelial cells to proliferate and generate tube-like structures, and to secrete pro-angiogenic cytokines and chemokines. Additionally, IL-1α attracts macrophages and collaborates with VEGF to enhance angiogenesis. Knockout mice for each of the different members of the family help reveal that IL-1β, and to a lesser extent IL-1α, are responsible for the pro-angiogenic effects, and therefore IL-1β depletion could reduce angiogenesis. The dual role of nitric oxide in tumor biology, as a cytotoxic factor for tumor cells, and as a pro-angiogenic factor, is summarized by Rahat and Hemmerlein (2013). The authors caution against the common use of iNOS immunohistochemical staining as a prognostic factor, as no correlation between survival rates, invasiveness or tumor recurrence after therapy is found. This is due to the ability of the microenvironment (e.g. hypoxia) to inhibit iNOS activity, even when it is highly expressed. Furthermore, tumor cells can manipulate their own expression of iNOS through the expression of microRNA-146a, to control their fate and evade macrophage-induced cell death, suggesting new possible therapeutic approaches. Two original papers demonstrate the pro-angiogenic role of additional, less studied proteins. Garcia-Areas et al. (2014) suggest that semphorin 7A (SEMA7A), a member of the semaphorin family involved in neuronal axonal guidance, is also a pro-angiogenic factor whose expression is increased in tumor-bearing mice. When triggered by SEMA7A, macrophages elevate secretion of angiogenic CXCL2/MIP-2 while silencing SEMA7A resulted in decreased tumor angiogenesis, and lower levels of CXCL2/MIP-2, CXCL1 and MMP-9. Amit-Cohen et al. (2013) report that EMMPRIN, a transmembranal protein that is overexpressed in tumor cells and have a pro-angiogenic activity, can induce the expression of MMP-9 and VEGF from macrophages in a secreted form instead of membranal form. Tumor cells and macrophages must be co-cultured for this effect, emphasizing the importance of their interaction. Secreted EMMPRIN levels were elevated through shedding-off of the membranal protein by the activity of a serine protease that was not yet identified. The final paper sheds light on the clinical aspect of vasculature re-growth after radiation therapy. Russell and Brown (2013) argue that because radiation destroys endothelial cells and tumor vasculature, tumor hypoxia is markedly increased resulting in induction of HIF-1 and HIF-2. These factors enhance the secretion of pro-angiogenic cytokines, chemokines and growth factors and recruit bone marrow-derived monocytes and macrophages which differentiate into TAMs and TEMs in the tumor. Thus, targeting the infiltration process after radiation therapy may improve the efficiency of treatment, prevent re-establishment of new vasculature and reduce tumor recurrence. Collectively, the articles in this topic highlight the importance and complexity of the interactions between macrophages and tumor cells in angiogenesis. Macrophages emerge as key regulators of the process because of their ability to communicate with tumor or stromal cells, sense the microenvironment and respond by inducing secretion of potent pro-angiogenic mediators. Some of these pro-angiogenic mediators and the triggers for their enhanced expression and secretion are at the focus of the current topic. Although more research is required, it is clear that tumor cell-macrophage interactions must precede and regulate the secretion phase—a point that was emphasized throughout this volume. This regulatory ability of the macrophages, and the fact that many mediators are both pro-inflammatory and pro-angiogenic, strongly links inflammation and angiogenesis together. Many inflammatory diseases, including cancer, are characterized by enhanced angiogenesis and a prominent macrophage component. The findings described here may be relevant for understanding macrophage-angiogenesis networks and potential therapy designs.

International audience; Kidney disease is a health condition affecting a high number of patients with an estimated worldwide prevalence of 10% (Jager et al., 2019). Kidney dysfunction and the resulting accumulation of uremic toxins and chronic inflammation contribute to secondary injury in organs like the heart, vessels, lungs, gut, brain, liver, among others (Malek, 2018; Shang et al., 2020; Ambruso et al., 2021; Lai et al., 2021). On the other hand, kidney disease might be the result of co-morbidities or due to a primary insult in another organ (Ronco et al., 2018). The mechanisms by which this kidney-distant organ communication occurs remain partially understood. This Research Topic compiled original investigation and review papers that explored the connection between the kidneys and other organs/co-morbidities and result in the proposal of novel biomarkers, therapeutic strategies and bring new insights into the molecular mechanisms linking kidney disease with other organs.therapeutic strategies and bring new insights into the molecular mechanisms linking kidney diseasewith other organs

Model organisms are often used in biological, medical and environmental research. Among insects, Drosophila melanogaster, Galleria mellonella, Apis mellifera, Bombyx mori, Periplaneta americana, and Locusta migratoria are often used. However, new model organisms still appear. In recent years, an increasing number of insect species has been suggested as model organisms in life sciences research due to their worldwide distribution and environmental significance, the possibility of extrapolating research studies to vertebrates and the relatively low cost of rearing. Beetles are the largest insect order, with their representative - Tribolium castaneum - being the first species with a completely sequenced genome, and seem to be emerging as new potential candidates for model organisms in various studies. Apart from T. castaneum, additional species representing various Coleoptera families, such as Nicrophorus vespilloides, Leptinotarsa decemlineata, Coccinella septempunctata, Poecilus cupreus, Tenebrio molitor and many others, have been used. They are increasingly often included in two major research aspects: biomedical and environmental studies. Biomedical studies focus mainly on unraveling mechanisms of basic life processes, such as feeding, neurotransmission or activity of the immune system, as well as on elucidating the mechanism of different diseases (neurodegenerative, cardiovascular, metabolic, or immunological) using beetles as models. Furthermore, pharmacological bioassays for testing novel biologically active substances in beetles have also been developed. It should be emphasized that beetles are a source of compounds with potential antimicrobial and anticancer activity. Environmental-based studies focus mainly on the development and testing of new potential pesticides of both chemical and natural origin. Additionally, beetles are used as food or for their valuable supplements. Different beetle families are also used as bioindicators. Another important research area using beetles as models is behavioral ecology studies, for instance, parental care. In this paper, we review the current knowledge regarding beetles as model organisms and their practical application in various fields of life science.

Atherogenesis, the formation of atherosclerotic plaques, is a complex process that involves several mechanisms, including endothelial dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, inflammation, and thrombosis. The pathogenesis and progression of atherosclerosis are explained differently by different scholars. One of the most common theories is the destruction of well-balanced homeostatic mechanisms, which incurs the oxidative stress. And oxidative stress is widely regarded as the redox status realized when an imbalance exists between antioxidant capability and activity species including reactive oxygen (ROS), nitrogen (RNS) and halogen species, non-radical as well as free radical species. This occurrence results in cell injury due to direct oxidation of cellular protein, lipid, and DNA or via cell death signaling pathways responsible for accelerating atherogenesis. This paper discusses inflammation, mitochondria, autophagy, apoptosis, and epigenetics as they induce oxidative stress in atherosclerosis, as well as various treatments for antioxidative stress that may prevent atherosclerosis.

The last two decades have generated numerous studies that show the close link between immune response and cancer progression in the mammalian system. In parallel, we have also witnessed significant progress in systemic approaches, such as high-throughput, multi-dimensional and dynamical analyses, in tackling biological complexities. We took this opportunity to organize a research topic that encompasses the current advances in immunology and cancer. The intention is to emphasize the importance of holistic view, and how such outlook can help shape the future of biological research. In total, our topic consists of 10 articles: five reviews, three research, and two perspectives. Owens and Naylor introduces the current understanding of cancer heterogeneity and stemness (Owens and Naylor, 2013). They surveyed a depth of recent literature that points to the presence of breast cancer stem cells (CSCs), which are responsible to mediate metastasis and are resistant to both radiation- and chemo-therapies. Although the classification of CSCs are currently based on the expression levels of cell surface markers CD44+CD24− and enzyme Aldehyde dehydrogenase (ALDH) activity, they note that the heterogeneity of single cancer cells makes this classification a nontrivial process. Thus, they ask for more mechanistic approaches to elucidate the origins for CSCs, so that more targeted novel therapies can be developed. In another survey of cancer mechanisms, Catalan et al. discuss the importance in understanding the connection between adipose tissue immunity and cancer (Catalan et al., 2013). They first quote numerous works that showed obesity-related chronic inflammation and, next, mention others that have demonstrated increased levels of immune cells and proinflammatory mediators in the expanded adipose tissue. Finally, they note specific obesity-associated adipokines that can promote tumor growth. Although the mechanistic links between obesity and cancer still remains unclear, more systemic analyses could reveal better hints in the future. Sangdun Choi and colleagues present a detailed update on the different structures of the crucial innate immune pattern recognition receptors, namely the Toll-like receptors (TLRs) (Manavalan et al., 2011). There are 13 known mammalian TLRs to-date, however, details of TLR12 and 13 is vastly unclear. Here, the authors cover the details of TLR1-11, especially on their structures, to understand the interactions of TLRs with their ligands and activators. They also argue that 3-D molecular simulations can be useful to make predictions on unknown interactions between TLRs and other possible novel interacting partners. Remaining on the same topic of TLRs, to investigate the differential roles of adaptor molecule MyD88 and MAP kinase activation in early and late immune response, which will influence the spatial movement of macrophages, Wenzel et al. developed an intelligent algorithm for automated image analysis (Wenzel et al., 2011). The novel approach is able to track cell spreading, after ligand stimulation, more accurately and with significant improvement in processing time, compared with manual techniques that are commonly adopted. Their main findings indicate that MyD88 is key for late spreading of macrophages while MAP kinase p38 is crucial for early spreading. Apart from innate immunity, another important aspect of our immune response is the orchestration of the adaptive immunity. T cells are lymphocytes that are central in the adaptive responses. In order to perform its specialized task, T cells need to differentiate into different lineages for executing distinct responses. In the unstimulated naive form, T cells exist mainly as two subtypes depending on their surface markers, CD4+, and CD8+ T cells. Ganusov and colleagues reviewed the differentiation lineages taken by CD4+ T cells on encountering MHC class II found on the surface of antigen-presenting cells such as macrophages or dendritic cells (Magombedze et al., 2013). Mainly, they emphasize on the functional plasticity of CD4+ T cells, and argue that understanding this will help treat diseases such as autoimmune diseases and allergic reactions where the elevated activity of differentiated T cells (e.g., T helper 17 or Th17 cells) may be reprogrammed to reach a different attractor state or back to its naive form that will not be injurious to the host. They acknowledged that computational or mathematical models can be useful for predicting how one could convert a particular T cell subset into another. A subsequent manuscript by Blair et al. reviews some of the most common mathematical and statistical approaches used for immune and cancer systems biology at different scales of biological modularization (Blair et al., 2012). Next, Hiroi and colleagues present a method to optimize the model parameters where experimental data are either sparse or noisy (Hiroi et al., 2014). They tested their method on well-established data on c-Myc and E2F transcriptional processes. The following article by Oyama and colleagues briefly discusses about recent high-throughput phosphoproteomics research (Kozuka-Hata et al., 2012). They describe the basic terminologies used and also highlight the importance of such methods for the development of large-scale signal transduction models for systemic interpretation of EGF signaling, TLR signaling or any other pathways of interest. Fitting with the theme of adopting systemic approaches for understanding immune and cancer response is the paper by Campbell et al. (2011). Here, they have studied the distinct roles of CD8+ T cells to the pathogenesis of cancer. Using in vivo derived quantitative data of tumor promoting Tag-expressing mice cells encountering CD8+ T cells, they developed a computational model to investigate the interaction pathways. Remarkably, using a simple ordinary differential equation model, the responses of CD8+ T cells to different perturbations in silico were consistent with matched experiments. However, from the model, it became clear that the proliferation and decay rates of CD8+ T cells were strongly constrained and hence, Tag-expressing mice cells become tolerant to tumors. Knowing such information a priori will surely aid researchers to understand and possibly avoid poor targets for regulating cancer progression. Finally, we conclude our collection with an interview with a prominent Japanese physicist, Kaneko (2011), who has switched his interest from pure theory to understanding complex living systems. In the article, he describes the reason behind his renewed interest, and the challenges facing theoreticians in biology. In summary, we believe the articles in “Advances in Systems Immunology and Cancer” research topic or e-book will bring continued interests for the development and utility of multidisciplinary approaches to tackle complex diseases.

The etiopathogenesis of many autoimmune disorders has not been identified. The aim of this paper is to focus on the involvement of bacterial exposure, as an environmental factor, in the pathogenesis of autoimmune pancreatitis (AIP), which is broadly categorized as autoimmune disorders involving pancreatic lesions. Avirulent and/or commensal bacteria, which may have an important role(s) as initiating/progressing factors in the pathogenesis of autoimmune disorder AIP, will be emphasized.