An Eclectic Cast of Cellular Actors Orchestrates Innate Immune Responses in the Mechanisms Driving Obesity and Metabolic Perturbation

The escalating problem of obesity and its multiple metabolic and cardiovascular complications threatens the health and longevity of humans throughout the world. The cause of obesity and one of its chief complications, insulin resistance, involves the participation of multiple distinct organs and cell types. From the brain to the periphery, cell-intrinsic and intercellular networks converge to stimulate and propagate increases in body mass and adiposity, as well as disturbances of insulin sensitivity. This review focuses on the roles of the cadre of innate immune cells, both those that are resident in metabolic organs and those that are recruited into these organs in response to cues elicited by stressors such as overnutrition and reduced physical activity. Beyond the typical cast of innate immune characters invoked in the mechanisms of metabolic perturbation in these settings, such as neutrophils and monocytes/macrophages, these actors are joined by bone marrow–derived cells, such as eosinophils and mast cells and the intriguing innate lymphoid cells, which are present in the circulation and in metabolic organ depots. Upon high-fat feeding or reduced physical activity, phenotypic modulation of the cast of plastic innate immune cells ensues, leading to the production of mediators that affect inflammation, lipid handling, and metabolic signaling. Furthermore, their consequent interactions with adaptive immune cells, including myriad T-cell and B-cell subsets, compound these complexities. Notably, many of these innate immune cell-elicited signals in overnutrition may be modulated by weight loss, such as that induced by bariatric surgery. Recently, exciting insights into the biology and pathobiology of these cell type–specific niches are being uncovered by state-of-the-art techniques such as single-cell RNA-sequencing. This review considers the evolution of this field of research on innate immunity in obesity and metabolic perturbation, as well as future directions.

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Engineering advanced logic and distributed computing in human CAR immune cells

Nature Communications ◽

10.1038/s41467-021-21078-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jang Hwan Cho ◽

Atsushi Okuma ◽

Katri Sofjan ◽

Seunghee Lee ◽

James J. Collins ◽

...

Keyword(s):

Immune Cells ◽

Communication Channel ◽

Immune Cell ◽

Cell Types ◽

Innate Immune ◽

Innate Immune Cells ◽

Complex Phenotypes ◽

Car T ◽

Different Cell Types ◽

Multiple Immune Cell

AbstractThe immune system is a sophisticated network of different cell types performing complex biocomputation at single-cell and consortium levels. The ability to reprogram such an interconnected multicellular system holds enormous promise in treating various diseases, as exemplified by the use of chimeric antigen receptor (CAR) T cells as cancer therapy. However, most CAR designs lack computation features and cannot reprogram multiple immune cell types in a coordinated manner. Here, leveraging our split, universal, and programmable (SUPRA) CAR system, we develop an inhibitory feature, achieving a three-input logic, and demonstrate that this programmable system is functional in diverse adaptive and innate immune cells. We also create an inducible multi-cellular NIMPLY circuit, kill switch, and a synthetic intercellular communication channel. Our work highlights that a simple split CAR design can generate diverse and complex phenotypes and provide a foundation for engineering an immune cell consortium with user-defined functionalities.

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The role of rare innate immune cells in Type 2 immune activation against parasitic helminths

Parasitology ◽

10.1017/s0031182017000488 ◽

2017 ◽

Vol 144 (10) ◽

pp. 1288-1301 ◽

Cited By ~ 19

Author(s):

LAUREN M. WEBB ◽

ELIA D. TAIT WOJNO

Keyword(s):

Immune Cells ◽

Low Frequency ◽

Cell Types ◽

Innate Immune ◽

Lymphoid Cells ◽

Innate Immune Cells ◽

Helminth Parasites ◽

Parasitic Helminths ◽

Group 2

SUMMARYThe complexity of helminth macroparasites is reflected in the intricate network of host cell types that participate in the Type 2 immune response needed to battle these organisms. In this context, adaptive T helper 2 cells and the Type 2 cytokines interleukin (IL)-4, IL-5, IL-9 and IL-13 have been the focus of research for years, but recent work has demonstrated that the innate immune system plays an essential role. Some innate immune cells that promote Type 2 immunity are relatively abundant, such as macrophages and eosinophils. However, we now appreciate that more rare cell types including group 2 innate lymphoid cells, basophils, mast cells and dendritic cells make significant contributions to these responses. These cells are found at low frequency but they are specialized to their roles – located at sites such as the skin, lung and gut, where the host combats helminth parasites. These cells respond rapidly and robustly to worm antigens and worm-induced damage to produce essential cytokines, chemokines, eicosanoids and histamine to activate damaged epithelium and to recruit other effectors. Thus, a greater understanding of how these cells operate is essential to understand how the host protects itself during helminth infection.

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Adipocytes, Innate Immunity and Obesity: A Mini-Review

Frontiers in Immunology ◽

10.3389/fimmu.2021.650768 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alecia M. Blaszczak ◽

Anahita Jalilvand ◽

Willa A. Hsueh

Keyword(s):

Adipose Tissue ◽

Immune System ◽

Immune Cells ◽

Adaptive Immune System ◽

Innate Immune ◽

Lymphoid Cells ◽

Innate Immune Cells ◽

Adaptive Immune

The role of adipose tissue (AT) inflammation in obesity and its multiple related-complications is a rapidly expanding area of scientific interest. Within the last 30 years, the role of the adipocyte as an endocrine and immunologic cell has been progressively established. Like the macrophage, the adipocyte is capable of linking the innate and adaptive immune system through the secretion of adipokines and cytokines; exosome release of lipids, hormones, and microRNAs; and contact interaction with other immune cells. Key innate immune cells in AT include adipocytes, macrophages, neutrophils, and innate lymphoid cells type 2 (ILC2s). The role of the innate immune system in promoting adipose tissue inflammation in obesity will be highlighted in this review. T cells and B cells also play important roles in contributing to AT inflammation and are discussed in this series in the chapter on adaptive immunity.

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Evidence for B cell maturation but not trained immunity in uninfected infants exposed to hepatitis C virus

Gut ◽

10.1136/gutjnl-2019-320269 ◽

2020 ◽

Vol 69 (12) ◽

pp. 2203-2213 ◽

Cited By ~ 1

Author(s):

Anton Lutckii ◽

Benedikt Strunz ◽

Anton Zhirkov ◽

Olga Filipovich ◽

Elena Rukoiatkina ◽

...

Keyword(s):

Immune System ◽

B Cells ◽

B Cell ◽

Immune Cells ◽

Immune Cell ◽

Innate Immune ◽

Cell Maturation ◽

Innate Immune Cells ◽

B Cell Maturation ◽

Exposed Uninfected

ObjectivesVertical transmission of hepatitis C virus (HCV) is rare compared with other chronic viral infections, despite that newborns have an immature, and possibly more susceptible, immune system. It further remains unclear to what extent prenatal and perinatal exposure to HCV affects immune system development in neonates.DesignTo address this, we studied B cells, innate immune cells and soluble factors in a cohort of 62 children that were either unexposed, exposed uninfected or infected with HCV. Forty of these infants were followed longitudinally from birth up until 18 months of age.ResultsAs expected, evidence for B cell maturation was observed with increased age in children, whereas few age-related changes were noticed among innate immune cells. HCV-infected children had a high frequency of HCV-specific IgG-secreting B cells. Such a response was also detected in some exposed but uninfected children but not in uninfected controls. Consistent with this, both HCV-exposed uninfected and HCV-infected infants had evidence of early B cell immune maturation with an increased proportion of IgA-positive plasma cells and upregulated CD40 expression. In contrast, actual HCV viraemia, but not mere exposure, led to alterations within myeloid immune cell populations, natural killer (NK) cells and a distinct soluble factor profile with increased levels of inflammatory cytokines and chemokines.ConclusionOur data reveal that exposure to, and infection with, HCV causes disparate effects on adaptive B cells and innate immune cell such as myeloid cells and NK cells in infants.

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The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

Thrombosis and Haemostasis ◽

10.1160/th12-09-0703 ◽

2013 ◽

Vol 109 (03) ◽

pp. 399-406 ◽

Cited By ~ 56

Author(s):

Triantafyllos Chavakis ◽

Jindrich Chmelar ◽

Kyoung-Jin Chung

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Immune Cells ◽

Cytotoxic T Cells ◽

Innate Immune ◽

Low Grade ◽

Innate Immune Cells ◽

Metabolic Complications ◽

Adaptive Immune Cells

SummaryObesity is characterised by a chronic state of low-grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue (AT) inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Intense efforts in the recent years have aimed at dissecting the pathophysiology of AT inflammation. The role of both innate and adaptive immune cells, such as macrophages or cytotoxic T cells in AT inflammation has been demonstrated. Besides these cells, more leukocyte subpopulations have been recently implicated in obesity, including neutrophils and eosinophils, mast cells, natural killer cells or dendritic cells. The involvement of multiple leukocyte subpopulations underlines the complexity of obesity-associated AT inflammation. In this review, we discuss the role of innate immune cells in AT inflammation, obesity and related metabolic disorders.

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Lipopolysaccharide modulates neutrophil recruitment and macrophage polarization on lymphatic vessels and impairs lymphatic function in rat mesentery

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00467.2015 ◽

2015 ◽

Vol 309 (12) ◽

pp. H2042-H2057 ◽

Cited By ~ 25

Author(s):

Sanjukta Chakraborty ◽

Scott D. Zawieja ◽

Wei Wang ◽

Yang Lee ◽

Yuan J. Wang ◽

...

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Contractile Activity ◽

Macrophage Polarization ◽

Lymphatic Vessels ◽

Innate Immune ◽

Innate Immune Cells ◽

Lymphatic Function ◽

Inflammatory Conditions ◽

Rat Mesentery

Impairment of the lymphatic system is apparent in multiple inflammatory pathologies connected to elevated endotoxins such as LPS. However, the direct mechanisms by which LPS influences the lymphatic contractility are not well understood. We hypothesized that a dynamic modulation of innate immune cell populations in mesentery under inflammatory conditions perturbs tissue cytokine/chemokine homeostasis and subsequently influences lymphatic function. We used rats that were intraperitoneally injected with LPS (10 mg/kg) to determine the changes in the profiles of innate immune cells in the mesentery and in the stretch-mediated contractile responses of isolated lymphatic preparations. Results demonstrated a reduction in the phasic contractile activity of mesenteric lymphatic vessels from LPS-injected rats and a severe impairment of lymphatic pump function and flow. There was a significant reduction in the number of neutrophils and an increase in monocytes/macrophages present on the lymphatic vessels and in the clear mesentery of the LPS group. This population of monocytes and macrophages established a robust M2 phenotype, with the majority showing high expression of CD163 and CD206. Several cytokines and chemoattractants for neutrophils and macrophages were significantly changed in the mesentery of LPS-injected rats. Treatment of lymphatic muscle cells (LMCs) with LPS showed significant changes in the expression of adhesion molecules, VCAM1, ICAM1, CXCR2, and galectin-9. LPS-TLR4-mediated regulation of pAKT, pERK pI-κB, and pMLC20 in LMCs promoted both contractile and inflammatory pathways. Thus, our data provide the first evidence connecting the dynamic changes in innate immune cells on or near the lymphatics and complex cytokine milieu during inflammation with lymphatic dysfunction.

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Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma

10.1101/248807 ◽

2018 ◽

Author(s):

Carlos R. Figueiredo ◽

Ricardo A. Azevedo ◽

Sasha Mousdell ◽

Pedro T. Resende-Lara ◽

Lucy Ireland ◽

...

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Metastatic Melanoma ◽

Immune Cells ◽

Tumour Microenvironment ◽

Innate Immune ◽

Innate Immune Cells ◽

Adaptive Immune Cells ◽

Cancer Immunotherapies

ABSTRACTMounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells’ immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

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A novel innate lymphoid cell delineates childhood autoimmune arthritis

10.1101/416784 ◽

2018 ◽

Author(s):

Martin Del Castillo Velasco-Herrera ◽

Matthew D Young ◽

Felipe A Vieira Braga ◽

Elizabeth C. Rosser ◽

Elena Miranda ◽

...

Keyword(s):

Autoimmune Disease ◽

Synovial Fluid ◽

Immune Cells ◽

Messenger Rna ◽

Cell Types ◽

Lymphoid Cells ◽

Autoimmune Arthritis ◽

Cellular Interactions ◽

Activated T Cells ◽

Adaptive Immune Cells

Inflammation in autoimmune disease is mediated by a complex network of interacting cells. Their identity and cross-talk are encoded in messenger RNA (mRNA). Juvenile idiopathic arthritis (JIA), a chronic autoimmune arthritis of childhood, is characterised by synovial inflammation with infiltration of both innate and adaptive immune cells1. Activated T cells play a role in disease2 but the cell types that drive the recruitment and activation of immune cells within the synovium are not known. Here, we utilised droplet-based and full length single cell mRNA sequencing to obtain a quantitative map of the cellular landscape of JIA. We studied 45,715 cells from the synovial fluid of inflamed knee joints and peripheral blood. We identified a population of synovial innate lymphoid cells (ILCs), shared across patients, that exhibited a unique transcriptional profile in comparison to canonical ILC subtypes. Validation at protein-level across a spectrum of autoimmune arthritides revealed that these ILCs are pathologically expanded in a particular type of JIA. Using statistical tools to assess cellular interactions in synovial fluid, ILCs emerged as a central node of communication, expressing the full repertoire of genes required to orchestrate and maintain the inflammatory milieu. Several ILC-mediated signalling pathways may lend themselves as novel therapeutic targets. Together our findings demonstrate a distinct ILC subtype associated with a tissue-specific childhood autoimmune disease.

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Elucidating the Innate Immunological Effects of Mild Magnetic Hyperthermia on U87 Human Glioblastoma Cells: An in vitro Study

10.20944/preprints202108.0494.v1 ◽

2021 ◽

Author(s):

Stefano Persano ◽

Francesco Vicini ◽

Alessandro Poggi ◽

Jordi Leonardo Castrillo Fernandez ◽

Giusy Maria Rita Rizzo ◽

...

Keyword(s):

Immune Cells ◽

Immune Cell ◽

Nk Cell ◽

Magnetic Hyperthermia ◽

Innate Immune ◽

Target Cells ◽

Innate Immune Cells ◽

Glioblastoma Cells ◽

Mild Hyperthermia ◽

Wide Range

Cancer immunotherapies are gaining a large popularity and many of them have been approved as standard second-line or in some cases even as first-line treatment for a wide range of cancers. However, immunotherapy has not shown a clinically relevant success in glioblastoma (GBM), principally due to the brain’s “immune-privileged” status and the peculiar tumor microenvironment (TME) of GBM featured by lack of presence of tumor-infiltrating lymphocytes and the establishment of immunosuppressive mechanisms. Emerging evidence has highlighted the key role played by innate immune cells in immunosurveillance and in initiating and driving immune responses against GBM. Immunogenic cell death (ICD) is a promising approach to elicit direct activation of the innate immune system by inducing in target cancer cells the expression of molecular signatures recognized through a repertoire of innate immune cell pattern recognition receptors (PRRs) by effector innate immune cells. Herein, we explored local mild thermal treatment, generated by using ultrasmall (size ~ 17 nm) cubic-shaped iron oxide nanoparticles exposed to an external alternating magnetic field (AMF), to induce ICD in U87 glioblastoma cells. In accordance with what has been previously observed with other types of tumors, we found that mild hyperthermia modulates the immunological profile of U87 glioblastoma cells by inducing stress-associated signals leading to enhanced phagocytosis and killing of U87 cells by macrophages. Finally, we demonstrated that mild magnetic hyperthermia has a modulatory effect on the expression of inhibitory and activating NK cell ligands on target cells. Interestingly, alteration in the expression of NK ligands, caused by mild hyperthermia treatment, in U87 glioblastoma cells, increased their susceptibility to NK cell killing and NK cell functionality. The overall findings demonstrate that mild magnetic hyperthermia stimulates ICD and sensitizes GBM cells to NK-mediated killing by inducing the upregulation of specific stress ligands, providing a novel immunotherapeutic approach for GBM treatment, with potential to synergize with existing NK cell-based therapies thus improving their therapeutic outcomes.

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The cell biology of inflammation: From common traits to remarkable immunological adaptations

The Journal of Cell Biology ◽

10.1083/jcb.202004003 ◽

2020 ◽

Vol 219 (7) ◽

Cited By ~ 1

Author(s):

Helen Weavers ◽

Paul Martin

Keyword(s):

Innate Immunity ◽

Cell Division ◽

Membrane Trafficking ◽

Immune Cells ◽

Cell Biology ◽

Foreign Bodies ◽

Cell Types ◽

Innate Immune ◽

Innate Immune Cells ◽

Starting Point

Tissue damage triggers a rapid and robust inflammatory response in order to clear and repair a wound. Remarkably, many of the cell biology features that underlie the ability of leukocytes to home in to sites of injury and to fight infection—most of which are topics of intensive current research—were originally observed in various weird and wonderful translucent organisms over a century ago by Elie Metchnikoff, the “father of innate immunity,” who is credited with discovering phagocytes in 1882. In this review, we use Metchnikoff’s seminal lectures as a starting point to discuss the tremendous variety of cell biology features that underpin the function of these multitasking immune cells. Some of these are shared by other cell types (including aspects of motility, membrane trafficking, cell division, and death), but others are more unique features of innate immune cells, enabling them to fulfill their specialized functions, such as encapsulation of invading pathogens, cell–cell fusion in response to foreign bodies, and their self-sacrifice as occurs during NETosis.

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