Shaping of Innate Immune Response by Fatty Acid Metabolite Palmitate

Innate immune cells monitor invading pathogens and pose the first-line inflammatory response to coordinate with adaptive immunity for infection removal. Innate immunity also plays pivotal roles in injury-induced tissue remodeling and the maintenance of tissue homeostasis in physiological and pathological conditions. Lipid metabolites are emerging as the key players in the regulation of innate immune responses, and recent work has highlighted the importance of the lipid metabolite palmitate as an essential component in this regulation. Palmitate modulates innate immunity not only by regulating the activation of pattern recognition receptors in local innate immune cells, but also via coordinating immunological activity in inflammatory tissues. Moreover, protein palmitoylation controls various cellular physiological processes. Herein, we review the updated evidence that palmitate catabolism contributes to innate immune cell-mediated inflammatory processes that result in immunometabolic disorders.

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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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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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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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Pregnancy alters innate immune responses to Zika virus infection in the genital tract

10.1101/828731 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kelsey E. Lesteberg ◽

Dana S. Fader ◽

J. David Beckham

Keyword(s):

Virus Infection ◽

Immune Responses ◽

Zika Virus ◽

Immune Cell ◽

Innate Immune ◽

Innate Immune Cells ◽

Innate Immune Responses ◽

Zikv Infection ◽

Zika Virus Infection ◽

Pregnant Mice

AbstractRecent outbreaks of Zika virus (ZIKV) have been associated with birth defects, including microcephaly and neurological impairment. However, the mechanisms which confer increased susceptibility to ZIKV during pregnancy remain unclear. We hypothesized that poor outcomes from ZIKV infection during pregnancy are due in part to pregnancy-induced alteration of innate immune cell frequencies and cytokine expression. To examine the impact of pregnancy on innate immune responses, we inoculated pregnant and non-pregnant female C57BL/6 mice with 5×105 FFU of ZIKV intravaginally. Innate immune cell frequencies and cytokine expression were measured by flow cytometry at day 3 post infection. Compared to non-pregnant mice, pregnant mice exhibited higher frequencies of uterine macrophages (CD68+) and tolerogenic dendritic cells (CD11c+ CD103+ and CD11c+ CD11b+). Additionally, ZIKV-infected pregnant mice had lower frequencies of CD45+ IL-12+ and CD11b+ IL-12+ cells in the uterus and spleen. These data show that pregnancy results in an altered innate immune response to ZIKV infection in the genital tract of mice and that pregnancy-associated immune modulation may play an important role in the severity of acute ZIKV infection.ImportancePregnant females longer duration that viremia following infection with Zika virus but the mechanism of this is not established. Innate immune cellular responses are important for controlling virus infection and are important for development and maintenance of pregnancy. Thus, the acute immune response to Zika virus during pregnancy may be altered so that the pregnancy can be maintained. To examine this interaction, we utilized a mouse model of Zika virus infection during pregnancy using intravaginal inoculation. We found that following Zika virus infection, pregnant mice exhibited increased expression of tolerant or non-inflammatory dendritic cells. Additionally, we found that pregnant mice have significantly depressed ability to secrete the cytokine IL-12 from innate immune cells in the uterus and the spleen while maintaining MHCII expression. These findings show that pregnancy-induced changes in the innate immune cells are biased towards tolerance and can result in decreased antigen-dependent stimulation of immune responses.

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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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Role of Macrophages and Microglia in Zebrafish Regeneration

International Journal of Molecular Sciences ◽

10.3390/ijms21134768 ◽

2020 ◽

Vol 21 (13) ◽

pp. 4768 ◽

Cited By ~ 4

Author(s):

Susanna R. Var ◽

Christine A. Byrd-Jacobs

Keyword(s):

Nervous System ◽

Immune Cells ◽

Immune Cell ◽

Innate Immune ◽

Inflammatory Processes ◽

The Central Nervous System ◽

And Function ◽

High Degree ◽

Human Nerve

Currently, there is no treatment for recovery of human nerve function after damage to the central nervous system (CNS), and there are limited regenerative capabilities in the peripheral nervous system. Since fish are known for their regenerative abilities, understanding how these species modulate inflammatory processes following injury has potential translational importance for recovery from damage and disease. Many diseases and injuries involve the activation of innate immune cells to clear damaged cells. The resident immune cells of the CNS are microglia, the primary cells that respond to infection and injury, and their peripheral counterparts, macrophages. These cells serve as key modulators of development and plasticity and have been shown to be important in the repair and regeneration of structure and function after injury. Zebrafish are an emerging model for studying macrophages in regeneration after injury and microglia in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. These fish possess a high degree of neuroanatomical, neurochemical, and emotional/social behavioral resemblance with humans, serving as an ideal simulator for many pathologies. This review explores literature on macrophage and microglial involvement in facilitating regeneration. Understanding innate immune cell behavior following damage may help to develop novel methods for treating toxic and chronic inflammatory processes that are seen in trauma and disease.

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Stress Hyperglycemia, Insulin Treatment, and Innate Immune Cells

International Journal of Endocrinology ◽

10.1155/2014/486403 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 41

Author(s):

Fangming Xiu ◽

Mile Stanojcic ◽

Li Diao ◽

Marc G. Jeschke

Keyword(s):

Insulin Resistance ◽

Innate Immunity ◽

Immune System ◽

Critical Illness ◽

Immune Cells ◽

Innate Immune System ◽

Insulin Treatment ◽

Innate Immune ◽

Morbidity And Mortality ◽

Innate Immune Cells

Hyperglycemia (HG) and insulin resistance are the hallmarks of a profoundly altered metabolism in critical illness resulting from the release of cortisol, catecholamines, and cytokines, as well as glucagon and growth hormone. Recent studies have proposed a fundamental role of the immune system towards the development of insulin resistance in traumatic patients. A comprehensive review of published literatures on the effects of hyperglycemia and insulin on innate immunity in critical illness was conducted. This review explored the interaction between the innate immune system and trauma-induced hypermetabolism, while providing greater insight into unraveling the relationship between innate immune cells and hyperglycemia. Critical illness substantially disturbs glucose metabolism resulting in a state of hyperglycemia. Alterations in glucose and insulin regulation affect the immune function of cellular components comprising the innate immunity system. Innate immune system dysfunction via hyperglycemia is associated with a higher morbidity and mortality in critical illness. Along with others, we hypothesize that reduction in morbidity and mortality observed in patients receiving insulin treatment is partially due to its effect on the attenuation of the immune response. However, there still remains substantial controversy regarding moderate versus intensive insulin treatment. Future studies need to determine the integrated effects of HG and insulin on the regulation of innate immunity in order to provide more effective insulin treatment regimen for these patients.

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Targeting CXCR4-dependent immunosuppressive Ly6Clow monocytes improves antiangiogenic therapy in colorectal cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1710754114 ◽

2017 ◽

Vol 114 (39) ◽

pp. 10455-10460 ◽

Cited By ~ 38

Author(s):

Keehoon Jung ◽

Takahiro Heishi ◽

Joao Incio ◽

Yuhui Huang ◽

Elizabeth Y. Beech ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Immune Cells ◽

Immune Cell ◽

Antiangiogenic Therapy ◽

Innate Immune ◽

Growth Delay ◽

Innate Immune Cells ◽

Tumor Growth Delay ◽

Anti Vegf

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1−/− mice), Ly6Chigh monocytes (CCR2−/− mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2–induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2–induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

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Reprogramming Interferon Regulatory Factor Signaling in Cardiometabolic Diseases

Physiology ◽

10.1152/physiol.00038.2016 ◽

2017 ◽

Vol 32 (3) ◽

pp. 210-223 ◽

Cited By ~ 9

Author(s):

Yaxing Zhang ◽

Hongliang Li

Keyword(s):

Innate Immunity ◽

Immune Responses ◽

Immune Cells ◽

Interferon Regulatory Factor ◽

Innate Immune ◽

Innate Immune Responses ◽

Regulatory Factor ◽

Cardiometabolic Diseases ◽

Evolutionarily Conserved

Interferon regulatory factors (IRFs) are evolutionarily conserved proteins expressed not only in immune cells but also in other tissues and organs outside the immune system. In this review, we discuss mechanisms responsible for IRF-mediated innate immune responses and the function and mechanism of IRFs in cardiometabolic diseases. We focus on the role of IRFs in innate immunity and cardiometabolic homeostasis, and highlight reprogrammed IRF signaling.

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