scholarly journals Endogenous Regulation and Pharmacological Modulation of Sepsis-Induced HMGB1 Release and Action: An Updated Review

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2220
Author(s):  
Cassie Shu Zhu ◽  
Wei Wang ◽  
Xiaoling Qiang ◽  
Weiqiang Chen ◽  
Xiqian Lan ◽  
...  
Keyword(s):  
Immune Cells ◽  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
High Mobility ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Pharmacological Modulation ◽  
Clinical Investigations ◽  
Bacterial Endotoxins ◽  
Necrosis Factor

Sepsis remains a common cause of death in intensive care units, accounting for approximately 20% of total deaths worldwide. Its pathogenesis is partly attributable to dysregulated inflammatory responses to bacterial endotoxins (such as lipopolysaccharide, LPS), which stimulate innate immune cells to sequentially release early cytokines (such as tumor necrosis factor (TNF) and interferons (IFNs)) and late mediators (such as high-mobility group box 1, HMGB1). Despite difficulties in translating mechanistic insights into effective therapies, an improved understanding of the complex mechanisms underlying the pathogenesis of sepsis is still urgently needed. Here, we review recent progress in elucidating the intricate mechanisms underlying the regulation of HMGB1 release and action, and propose a few potential therapeutic candidates for future clinical investigations.

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

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.

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

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 1018 ◽  
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.

scholarly journals Tumor Necrosis Factor (TNF) Receptor Shedding Controls Thresholds of Innate Immune Activation That Balance Opposing TNF Functions in Infectious and Inflammatory Diseases

2004 ◽  
Vol 200 (3) ◽  
pp. 367-376 ◽  
Author(s):  
Sofia Xanthoulea ◽  
Manolis Pasparakis ◽  
Stavroula Kousteni ◽  
Cord Brakebusch ◽  
David Wallach ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Bacterial Infections ◽  
Tumor Necrosis ◽  
Inflammatory Responses ◽  
Endotoxic Shock ◽  
Innate Immune ◽  
Disease Assessment ◽  
Recurrent Fever ◽  
Receptor Shedding ◽  
Necrosis Factor

Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor–dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.

Cytokine release from innate immune cells: association with diverse membrane trafficking pathways

Blood ◽  
2011 ◽  
Vol 118 (1) ◽  
pp. 9-18 ◽  
Author(s):  
Paige Lacy ◽  
Jennifer L. Stow
Keyword(s):  
Membrane Trafficking ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Cell Types ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Cytokine Release ◽  
Research Findings ◽  
Specific Receptors ◽  
Different Cell Types

AbstractCytokines released from innate immune cells play key roles in the regulation of the immune response. These intercellular messengers are the source of soluble regulatory signals that initiate and constrain inflammatory responses to pathogens and injury. Although numerous studies describe detailed signaling pathways induced by cytokines and their specific receptors, there is little information on the mechanisms that control the release of cytokines from different cell types. Indeed, the pathways, molecules, and mechanisms of cytokine release remain a “black box” in immunology. Here, we review research findings and new approaches that have begun to generate information on cytokine trafficking and release by innate immune cells in response to inflammatory or infectious stimuli. Surprisingly complex machinery, multiple organelles, and specialized membrane domains exist in these cells to ensure the selective, temporal, and often polarized release of cytokines in innate immunity.

scholarly journals Host–Microbe Interactions and Gut Health in Poultry—Focus on Innate Responses

2019 ◽  
Vol 7 (5) ◽  
pp. 139 ◽  
Author(s):  
Leon J. Broom
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Inflammatory Responses ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Gut Health ◽  
Mucosal Surfaces ◽  
Microbe Interactions ◽  
Host Microbe Interactions

Commercial poultry are continually exposed to, frequently pathogenic, microorganisms, usually via mucosal surfaces such as the intestinal mucosa. Thus, understanding host–microbe interactions is vital. Many of these microorganisms may have no or limited contact with the host, while most of those interacting more meaningfully with the host will be dealt with by the innate immune response. Fundamentally, poultry have evolved to have immune responses that are generally appropriate and adequate for their acquired microbiomes, although this is challenged by commercial production practices. Innate immune cells and their functions, encompassing inflammatory responses, create the context for neutralising the stimulus and initiating resolution. Dysregulated inflammatory responses can be detrimental but, being a highly conserved biological process, inflammation is critical for host defence. Heterogeneity and functional plasticity of innate immune cells is underappreciated and offers the potential for (gut) health interventions, perhaps including exogenous opportunities to influence immune cell metabolism and thus function. New approaches could focus on identifying and enhancing decisive but less harmful immune processes, improving the efficiency of innate immune cells (e.g., targeted, efficient microbial killing) and promoting phenotypes that drive resolution of inflammation. Breeding strategies and suitable exogenous interventions offer potential solutions to enhance poultry gut health, performance and welfare.

scholarly journals The Impact of Nanoparticles on Innate Immune Activation by Live Bacteria

2020 ◽  
Vol 21 (24) ◽  
pp. 9695
Author(s):  
Benjamin J. Swartzwelter ◽  
Alexandra C. Fux ◽  
Litty Johnson ◽  
Elmer Swart ◽  
Sabine Hofer ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Responses ◽  
Particle Surface ◽  
Modern Technology ◽  
Innate Immune ◽  
Engineered Nanoparticles ◽  
Immune Memory ◽  
Innate Immune Cells ◽  
Live Bacteria ◽  
The Impact

The innate immune system evolved to detect and react against potential dangers such as bacteria, viruses, and environmental particles. The advent of modern technology has exposed innate immune cells, such as monocytes, macrophages, and dendritic cells, to a relatively novel type of particulate matter, i.e., engineered nanoparticles. Nanoparticles are not inherently pathogenic, and yet cases have been described in which specific nanoparticle types can either induce innate/inflammatory responses or modulate the activity of activated innate cells. Many of these studies rely upon activation by agonists of toll-like receptors, such as lipopolysaccharide or peptidoglycan, instead of the more realistic stimulation by whole live organisms. In this review we examine and discuss the effects of nanoparticles on innate immune cells activated by live bacteria. We focus in particular on how nanoparticles may interfere with bacterial processes in the context of innate activation, and confine our scope to the effects due to particles themselves, rather than to molecules adsorbed on the particle surface. Finally, we examine the long-lasting consequences of coexposure to nanoparticles and bacteria, in terms of potential microbiome alterations and innate immune memory, and address nanoparticle-based vaccine strategies against bacterial infection.

scholarly journals A role for BLyS in the activation of innate immune cells

Blood ◽  
2006 ◽  
Vol 108 (8) ◽  
pp. 2687-2694 ◽  
Author(s):  
Sook Kyung Chang ◽  
Bonnie K. Arendt ◽  
Jaime R. Darce ◽  
Xiaosheng Wu ◽  
Diane F. Jelinek
Keyword(s):  
Cell Surface ◽  
Immune Cells ◽  
B Lymphocyte ◽  
Costimulatory Molecule ◽  
Human Monocyte ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Adaptive Immune Cells ◽  
B Lymphocyte Stimulator ◽  
Necrosis Factor

AbstractB-lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (TNF) ligand superfamily. Although BLyS costimulates adaptive immune cells, the ability of BLyS to stimulate innate immune cells has not been described. Here, we show that BLyS strongly induces human monocyte survival, and activation as measured by proinflammatory cytokine secretion and up-regulation of costimulatory molecule expression. In addition, monocytes cultured with BLyS differentiated into macrophage-like cells. Regarding BLyS receptor(s) expression, freshly isolated monocytes bound low levels of exogenous BLyS and expressed primarily intracellular TACI, and cell surface TACI levels increased following monocyte activation. Of interest, bone marrow monocytes from some multiple myeloma patients expressed significant levels of cell surface TACI at isolation. Our findings indicate that BLyS plays a role in activating innate immune cells. Moreover, this study may explain more clearly why high BLyS production is often correlated with certain inflammatory autoimmune diseases and B-lymphocyte malignancies.

scholarly journals AB0693 TIM-3-EXPRESSING NEUTROPHILS AS A NOVEL INDICATOR TO ASSESS DISEASE ACTIVITY AND SEVERITY IN ANKYLOSING SPONDYLITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1641.1-1642
Author(s):  
X. Huang ◽  
T. Li ◽  
J. Chen ◽  
Y. Wang ◽  
S. Chen ◽  
...  
Keyword(s):  
Ankylosing Spondylitis ◽  
Disease Activity ◽  
Immune Cells ◽  
Inflammatory Responses ◽  
Clinical Manifestations ◽  
Chronic Inflammatory Disease ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Bacterial Killing ◽  
Markers Of Inflammation

Background:Ankylosing spondylitis (AS) is a type of chronic inflammatory disease that compromises the axial skeleton and sacroiliac joints. Many studies have shown that neutrophils play an important roles in the inflammatory process of AS. However, the immunomodulatory roles and mechanisms of neutrophils in AS are poorly understood. T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) has been reported as an important regulatory molecule, expressed and regulated on different innate immune cells, plays a pivotal role in several autoimmunity diseases. Recent study indicates that Tim3 is also expressed on neutrophils. However, the frequency and roles of Tim3-expressing neutrophils in AS was not clear.Objectives:In this study, we investigated the expression of Tim3 on neutrophils in AS patients and analyzed the correlation between the level of Tim3-expressing neutrophils and the disease activity of AS.Methods:AS Patients were recruited from Guangdong Second Provincial General Hospital (n=49). Age/sex-matched volunteers as Healthy controls (HC) (n=39). The medical history, clinical manifestations, physical examination, laboratory measurements were recorded. The expression of costimulatory molecules including programmed death 1 (PD-1), Tim-3 on neutrophils were determined by flow cytometry. The frequencies of Tim3-expressing neutrophils in AS patients were further analyzed for their correlation with markers of inflammation ESR and CRP, disease activity and severity of AS.Results:The expression of Tim3 on neutrophils in patients with AS was increased compared to the HC (Figure 1A). The frequency of Tim3-expressing neutrophils in patients with AS showed an positive correlation with ESR, CRP and ASAS-endorsed disease activity score (ASDAS) (Figure 1B). Moreover, the frequency of Tim3-expressing neutrophils in active patients(ASDAS≥1.3) was increased as compare with the inactive patients (ASDAS<1.3) (Figure 1C).Conclusion:Increased Tim-3 expression on neutrophils may be a novel indicator to assess disease activity and severity in AS, which may serves as a negative feedback mechanism preventing potential tissue damage caused by excessive inflammatory responses in AS patients.References:[1]Han, G., Chen, G., Shen, B. & Li, Y., Tim-3: an activation marker and activation limiter of innate immune cells.FRONT IMMUNOL4449 (2013).[2]Vega-Carrascal, I.et al., Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram-negative bacterial killing: an effect abrogated within the cystic fibrosis lung.J IMMUNOL1922418 (2014).Figure 1.(A)The expression of Tim3 on neutrophils in AS and HC.(B)The correction between Tim3-expressing neutrophils and ESR,CRP,ASDAS.(C) The expression of Tim3 on neutrophils in active and inactive patients.Disclosure of Interests:None declared

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