Interaction between Cannabinoid System and Toll-Like Receptors Controls Inflammation

Since the discovery of the endocannabinoid system consisting of cannabinoid receptors, endogenous ligands, and biosynthetic and metabolizing enzymes, interest has been renewed in investigating the promise of cannabinoids as therapeutic agents. Abundant evidence indicates that cannabinoids modulate immune responses. An inflammatory response is triggered when innate immune cells receive a danger signal provided by pathogen- or damage-associated molecular patterns engaging pattern-recognition receptors. Toll-like receptor family members are prominent pattern-recognition receptors expressed on innate immune cells. Cannabinoids suppress Toll-like receptor-mediated inflammatory responses. However, the relationship between the endocannabinoid system and innate immune system may not be one-sided. Innate immune cells express cannabinoid receptors and produce endogenous cannabinoids. Hence, innate immune cells may play a role in regulating endocannabinoid homeostasis, and, in turn, the endocannabinoid system modulates local inflammatory responses. Studies designed to probe the interaction between the innate immune system and the endocannabinoid system may identify new potential molecular targets in developing therapeutic strategies for chronic inflammatory diseases. This review discusses the endocannabinoid system and Toll-like receptor family and evaluates the interaction between them.

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Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

10.20944/preprints202003.0254.v1 ◽

2020 ◽

Author(s):

Abigail Elliot ◽

Henna Myllymäki ◽

Yi Feng

Keyword(s):

Immune Cells ◽

Cancer Biology ◽

Inflammatory Responses ◽

Live Imaging ◽

Innate Immune ◽

Leukocyte Recruitment ◽

Innate Immune Cells ◽

Neoplastic Cells ◽

Tumour Development ◽

Tumour Initiation

The zebrafish is now an important model organism for cancer biology studies and provides some unique and complementary opportunities in comparison to the mammalian equivalent. The translucency of zebrafish has allowed in vivo live imaging studies of tumour initiation and progression at the cellular level thus providing novel insights into our understanding of cancer. Here we summarise and discuss available transgenic zebrafish tumour models and what we have gleaned from them with respect to cancer inflammation. In particular, we focus on the host inflammatory response toward transformed cells during the pre-neoplastic stage of tumour development. We discuss features of tumour associated macrophages and neutrophils in mammalian models and present evidence which supports the idea that these inflammatory cells promote early stage tumour development and progression. Direct live imaging of tumour initiation in zebrafish models has shown that the intrinsic inflammation induced by pre-neoplastic cells is tumour promoting. Signals mediating leukocyte recruitment to pre-neoplastic cells in zebrafish correspond to signals mediating leukocyte recruitment in mammalian tumours. The activation state of macrophages and neutrophils recruited to pre-neoplastic cells appears to be heterogenous, as seen in mammalian models, which provides an opportunity to study the plasticity of innate immune cells during tumour initiation. Although several potential mechanisms are described that might mediate the trophic function of innate immune cells during tumour initiation in zebrafish, there are several unknowns that are yet to be resolved. Rapid advancement of genetic tools and imaging technologies for zebrafish will facilitate research into the mechanisms that modulate leukocyte function during tumour initiation and identify targets for cancer prevention.

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Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

Cells ◽

10.3390/cells9041018 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1018 ◽

Cited By ~ 1

Author(s):

Abigail Elliot ◽

Henna Myllymäki ◽

Yi Feng

Keyword(s):

Immune Cells ◽

Cancer Biology ◽

Inflammatory Responses ◽

Live Imaging ◽

Innate Immune ◽

Leukocyte Recruitment ◽

Innate Immune Cells ◽

Neoplastic Cells ◽

Tumour Development ◽

Tumour Initiation

The zebrafish is now an important model organism for cancer biology studies and provides unique and complementary opportunities in comparison to the mammalian equivalent. The translucency of zebrafish has allowed in vivo live imaging studies of tumour initiation and progression at the cellular level, providing novel insights into our understanding of cancer. Here we summarise the available transgenic zebrafish tumour models and discuss what we have gleaned from them with respect to cancer inflammation. In particular, we focus on the host inflammatory response towards transformed cells during the pre-neoplastic stage of tumour development. We discuss features of tumour-associated macrophages and neutrophils in mammalian models and present evidence that supports the idea that these inflammatory cells promote early stage tumour development and progression. Direct live imaging of tumour initiation in zebrafish models has shown that the intrinsic inflammation induced by pre-neoplastic cells is tumour promoting. Signals mediating leukocyte recruitment to pre-neoplastic cells in zebrafish correspond to the signals that mediate leukocyte recruitment in mammalian tumours. The activation state of macrophages and neutrophils recruited to pre-neoplastic cells in zebrafish appears to be heterogenous, as seen in mammalian models, which provides an opportunity to study the plasticity of innate immune cells during tumour initiation. Although several potential mechanisms are described that might mediate the trophic function of innate immune cells during tumour initiation in zebrafish, there are several unknowns that are yet to be resolved. Rapid advancement of genetic tools and imaging technologies for zebrafish will facilitate research into the mechanisms that modulate leukocyte function during tumour initiation and identify targets for cancer prevention.

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Toll-Like Receptor 8 Agonist and Bacteria Trigger Potent Activation of Innate Immune Cells in Human Liver

PLoS Pathogens ◽

10.1371/journal.ppat.1004210 ◽

2014 ◽

Vol 10 (6) ◽

pp. e1004210 ◽

Cited By ~ 128

Author(s):

Juandy Jo ◽

Anthony T. Tan ◽

James E. Ussher ◽

Elena Sandalova ◽

Xin-Zi Tang ◽

...

Keyword(s):

Immune Cells ◽

Human Liver ◽

Innate Immune ◽

Innate Immune Cells ◽

Toll Like Receptor

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The IκB-Protein BCL-3 Controls MAPK Activity by Promoting TPL-2 Degradation in the Nucleus

10.1101/373209 ◽

2018 ◽

Author(s):

Patricia E. Collins ◽

Domenico Somma ◽

David Kerrigan ◽

Felicity Herrington ◽

Karen R. Keeshan ◽

...

Keyword(s):

Immune Cells ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Primary Site ◽

Innate Immune ◽

Innate Immune Cells ◽

Nucleocytoplasmic Shuttling ◽

Activation Threshold ◽

Invasive Pathogens ◽

Mapk Activity

AbstractThe ability of the innate immune system to distinguish between low level microbial presence and invasive pathogens is fundamental for immune homeostasis and immunity. However, the molecular mechanisms underlying threat discrimination by innate immune cells are not clearly defined. Here we describe the integration of the NF-ĸB and MAPK pathways in the nucleus by the IĸB protein BCL-3 and the MAP3K TPL-2. Our data reveals that TPL-2 is a nucleocytoplasmic shuttling protein and demonstrates that the nucleus is the primary site for TPL-2 ubiquitination and proteasomal degradation. BCL-3 promotes TPL-2 degradation through interaction in the nucleus. As a consequence, Bcl3-/- macrophages have increased TPL-2 stability and MAPK activity following TLR stimulation. The enhanced stability of TPL-2 in Bcl3-/- macrophages lowers the MAPK activation threshold and the level of TLR ligand required to initiate an inflammatory response. This study establishes the nucleus as a key regulatory site for TLR-induced MAPK activity and identifies BCL-3 as a regulator of the cellular decision to initiate inflammation

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A Novel Regulatory Player in the Innate Immune System: Long Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms22179535 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9535

Author(s):

Yuhuai Xie ◽

Yuanyuan Wei

Keyword(s):

Immune System ◽

Immune Cells ◽

Innate Immune System ◽

Molecular Mechanisms ◽

Innate Immune ◽

Innate Immune Cells ◽

Immune Mediated ◽

Development And Differentiation ◽

Non Coding Rnas ◽

And Function

Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.

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Immune cells—A curse and a blessing!

Journal of Experimental Medicine ◽

10.1084/jem.20210590 ◽

2021 ◽

Vol 218 (6) ◽

Author(s):

Valbona Mirakaj

Keyword(s):

Cardiovascular Disease ◽

Immune System ◽

Immune Cells ◽

Innate Immune System ◽

Innate Immune ◽

Innate Immune Cells ◽

The Impact

Innate immune cells are crucial in the development and regulation of cardiovascular disease. In this issue, two groups, Davis et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20201839) and Li et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210008) describe the impact of the innate immune system on the development of cardiovascular disease.

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Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment

Cancers ◽

10.3390/cancers12082226 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2226

Author(s):

Israa Shihab ◽

Bariaa A. Khalil ◽

Noha Mousaad Elemam ◽

Ibrahim Y. Hachim ◽

Mahmood Yaseen Hachim ◽

...

Keyword(s):

Breast Cancer ◽

Immune System ◽

Tumor Microenvironment ◽

Nk Cells ◽

Immune Cells ◽

Innate Immune System ◽

Adaptive Immune System ◽

Innate Immune ◽

Innate Immune Cells ◽

Cancer Microenvironment

The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the innate immune system that accumulate in the tumor microenvironment such as breast cancer. These cells induce inflammation in situ by secreting cytokines and chemokines that promote tumor growth and progression, in addition to orchestrating the activities of other immune cells. In breast cancer microenvironment, innate immune cells are skewed towards immunosuppression that may lead to tumor evasion. However, the mechanisms by which immune cells could interact with breast cancer cells are complex and not fully understood. Therefore, the importance of the mammary tumor microenvironment in the development, growth, and progression of cancer is widely recognized. With the advances of using bioinformatics and analyzing data from gene banks, several genes involved in NK cells of breast cancer individuals have been identified. In this review, we discuss the activities of certain genes involved in the cross-talk among NK cells and breast cancer. Consequently, altering tumor immune microenvironment can make breast tumors more responsive to immunotherapy.

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The Role of Syk/CARD9-Coupled C-Type Lectin Receptors in Immunity toMycobacterium tuberculosisInfections

Clinical and Developmental Immunology ◽

10.1155/2010/567571 ◽

2010 ◽

Vol 2010 ◽

pp. 1-9 ◽

Cited By ~ 27

Author(s):

Mohlopheni Jackson Marakalala ◽

Lisa M. Graham ◽

Gordon D. Brown

Keyword(s):

Immune Response ◽

Pattern Recognition ◽

Mycobacterium Tuberculosis ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Lectin Receptors ◽

Molecular Patterns

There is increasing interest in understanding the mechanisms underlying the interactions that occur betweenMycobacterium tuberculosisand host innate immune cells. These cells express pattern recognition receptors (PRRs) which recognise mycobacterial pathogen-associated molecular patterns (PAMPs) and which can influence the host immune response to the infection. Although many of the PRRs appear to be redundant in the control ofM. tuberculosisinfectionin vivo, recent discoveries have revealed a key, nonredundant, role of the Syk/CARD9 signalling pathway in antimycobacterial immunity. Here we review these discoveries, as well as recent data investigating the role of the Syk/CARD9-coupled PRRs that have been implicated in mycobacterial recognition, including Dectin-1 and Mincle.

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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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