Neutrophils in acute inflammation - current concepts and translational implications

Modulation of neutrophil recruitment and function is crucial for targeting inflammatory cells to sites of infection to combat invading pathogens while at the same time limiting host tissue injury or autoimmunity. The underlying mechanisms regulating recruitment of neutrophils, one of the most abundant inflammatory cells, have gained increasing interest over the years. The previously described classical recruitment cascade of leukocytes has been extended to include not only capturing, rolling, adhesion, crawling and transmigration but furthermore a reverse-transmigration step that is crucial for balancing immune defense and control of remote organ endothelial leakage. Current developments in the field emphasize the importance of cellular interplay, tissue-environmental cues, circadian rhythmicity, detection of neutrophil phenotypes, differential chemokine sensing, and contribution of distinct signaling components to receptor activation and integrin conformations. Use of therapeutics modulating neutrophil activation responses as well as mutations causing dysfunctional neutrophil receptors and impaired signaling cascades have been defined in translational animal models. Human correlates of such mutations result in increased susceptibility to infections or organ damage. This review focuses on current advances in the understanding of the regulation of neutrophil recruitment and functionality and translational implications of current discoveries in the field with a focus on acute inflammation and sepsis.

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Mired in the glomeruli - Witnessing Live Neutrophil Recruitment in the Kidney

AJP Cell Physiology ◽

10.1152/ajpcell.00429.2020 ◽

2021 ◽

Author(s):

Pei Xiong Liew

Keyword(s):

Intracellular Signaling ◽

Immune Cell ◽

Tissue Injury ◽

Neutrophil Recruitment ◽

Proliferative Glomerulonephritis ◽

Cellular Infiltrate ◽

Live Animal ◽

Effector Cells ◽

Surface Molecules ◽

And Function

Inflammation of the kidney is a key contributor to proliferative glomerulonephritis and kidney damage during glomerulonephritis can lead to renal failure. The immune response associated with glomerulonephritis episodes are a major determinant of patient outcomes and understanding this response is paramount for effective therapeutic treatment. Neutrophils are the first responders to sites of infection or tissue injury and is a significant cellular infiltrate during proliferative glomerulonephritis. This immune cell was initially recognized as 'blunt' nonspecific effector cells that were recruited to kill pathogens and then die quickly. However, recent studies have shown that the behavior and function of neutrophils to be substantially more complex. Neutrophil recruitment to inflammatory sites must be carefully regulated so that these potent cells accurately arrive at tissue sites and perform their functions without non-specific injury to other locations. As the kidney contains unique microvasculature befitting their specialized role in blood filtration, the recruitment of neutrophils in the renal environment differs from other organs. This mini-review will describe how advances in live animal (intravital) imaging led to the discovery of novel recruitment pathways in the kidney, particularly in the glomeruli, and highlight these differences to canonical neutrophil recruitment. In addition, molecular engagement of surface molecules that lead to intracellular signaling, which is followed by neutrophil capture in the glomeruli, is also briefly discussed. Finally, the contribution of other immune cells in renal neutrophil recruitment, the fate of the emigrated neutrophils after inflammation and the relevance of mouse models compared to human glomerulonephritides will also be explored.

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Fibroblast-specific IL11 signaling is required for lung fibrosis and inflammation

10.1101/801852 ◽

2019 ◽

Cited By ~ 3

Author(s):

Benjamin Ng ◽

Jinrui Dong ◽

Sivakumar Viswanathan ◽

Anissa A. Widjaja ◽

Bhairav S. Paleja ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Lung Fibrosis ◽

Immune Cell ◽

Tissue Injury ◽

Inflammatory Cells ◽

Organ Damage ◽

Lung Damage ◽

Lung Fibroblasts ◽

Stromal Compartment ◽

Erk Activation

ABSTRACTTissue injury leads to activation of resident stromal, parenchymal and immune cells to initiate reparative processes that, if unresolved, can lead to fibrosis and organ damage. The directionality of effect between fibrosis and inflammation in the lung has been a point of debate for many years. Here, we tested the hypothesis that Interleukin 11 (IL11) signaling in fibroblasts is of primary importance for pulmonary fibrosis and that this event is upstream of lung inflammation. We generated mice with loxP-flanked Il11ra1 alleles and crossed them to a Col1a2-CreERT strain to enable Il11ra1 deletion in adult fibroblasts (Il11ra1-CKO mice). Lung fibroblasts from Il11ra1-CKO mice were selectively deleted for Il11ra1 and refractory to TGFβ1 stimulation. In the mouse model of bleomycin-induced lung fibrosis, Il11ra1-CKO mice had markedly reduced pulmonary fibrosis and lesser lung damage, which was accompanied by diminished ERK activation in the stromal compartment. Bleomycin lung injury in Il11ra1-CKO mice was also associated with diminished STAT3 activation in inflammatory cells, fewer pulmonary immune cell infiltrates and almost complete inhibition of NF-kB activation. These data reveal an essential role for IL11 signaling in fibroblasts for lung fibrosis and show that inflammation in the lung can be secondary to stromal activation.

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Targeting the PAC1 Receptor for Neurological and Metabolic Disorders

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190709092647 ◽

2019 ◽

Vol 19 (16) ◽

pp. 1399-1417 ◽

Cited By ~ 6

Author(s):

Chenyi Liao ◽

Mathilde P. de Molliens ◽

Severin T. Schneebeli ◽

Matthias Brewer ◽

Gaojie Song ◽

...

Keyword(s):

Rational Design ◽

Metabolic Diseases ◽

Structural Information ◽

Tissue Injury ◽

Current Knowledge ◽

Biological Activities ◽

Receptor Activation ◽

Pac1 Receptor ◽

Activation Mechanisms ◽

And Function

The pituitary adenylate cyclase-activating polypeptide (PACAP)-selective PAC1 receptor (PAC1R, ADCYAP1R1) is a member of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of G protein-coupled receptors (GPCRs). PAC1R has been shown to play crucial roles in the central and peripheral nervous systems. The activation of PAC1R initiates diverse downstream signal transduction pathways, including adenylyl cyclase, phospholipase C, MEK/ERK, and Akt pathways that regulate a number of physiological systems to maintain functional homeostasis. Accordingly, at times of tissue injury or insult, PACAP/PAC1R activation of these pathways can be trophic to blunt or delay apoptotic events and enhance cell survival. Enhancing PAC1R signaling under these conditions has the potential to mitigate cellular damages associated with cerebrovascular trauma (including stroke), neurodegeneration (such as Parkinson’s and Alzheimer's disease), or peripheral organ insults. Conversely, maladaptive PACAP/PAC1R signaling has been implicated in a number of disorders, including stressrelated psychopathologies (i.e., depression, posttraumatic stress disorder, and related abnormalities), chronic pain and migraine, and metabolic diseases; abrogating PAC1R signaling under these pathological conditions represent opportunities for therapeutic intervention. Given the diverse PAC1R-mediated biological activities, the receptor has emerged as a relevant pharmaceutical target. In this review, we first describe the current knowledge regarding the molecular structure, dynamics, and function of PAC1R. Then, we discuss the roles of PACAP and PAC1R in the activation of a variety of signaling cascades related to the physiology and diseases of the nervous system. Lastly, we examine current drug design and development of peptides and small molecules targeting PAC1R based on a number of structure- activity relationship studies and key pharmacophore elements. At present, the rational design of PAC1R-selective peptide or small-molecule therapeutics is largely hindered by the lack of structural information regarding PAC1R activation mechanisms, the PACAP-PAC1R interface, and the core segments involved in receptor activation. Understanding the molecular basis governing the PACAP interactions with its different cognate receptors will undoubtedly provide a basis for the development and/or refinement of receptor-selective therapeutics.

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Transcription Factor Nrf2 Regulates Inflammation by Mediating the Effect of 15-Deoxy-Δ12,14-Prostaglandin J2

Molecular and Cellular Biology ◽

10.1128/mcb.24.1.36-45.2004 ◽

2004 ◽

Vol 24 (1) ◽

pp. 36-45 ◽

Cited By ~ 298

Author(s):

Ken Itoh ◽

Mie Mochizuki ◽

Yukio Ishii ◽

Tetsuro Ishii ◽

Takahiro Shibata ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Acute Inflammation ◽

Inflammatory Cells ◽

Peritoneal Macrophages ◽

Neutrophil Recruitment ◽

Heme Oxygenase 1 ◽

Mouse Peritoneal Macrophages ◽

Pleural Lavage ◽

Deficient Mice

ABSTRACT Activated macrophages express high levels of Nrf2, a transcription factor that positively regulates the gene expression of antioxidant and detoxication enzymes. In this study, we examined how Nrf2 contributes to the anti-inflammatory process. As a model system of acute inflammation, we administered carrageenan to induce pleurisy and found that in Nrf2-deficient mice, tissue invasion by neutrophils persisted during inflammation and the recruitment of macrophages was delayed. Using an antibody against 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), it was observed that macrophages from pleural lavage accumulate 15d-PGJ2. We show that in mouse peritoneal macrophages 15d-PGJ2 can activate Nrf2 by forming adducts with Keap1, resulting in an Nrf2-dependent induction of heme oxygenase 1 and peroxiredoxin I (PrxI) gene expression. Administration of the cyclooxygenase 2 inhibitor NS-398 to mice with carrageenan-induced pleurisy caused persistence of neutrophil recruitment and, in macrophages, attenuated the 15d-PGJ2 accumulation and PrxI expression. Administration of 15d-PGJ2 into the pleural space of NS-398-treated wild-type mice largely counteracted both the decrease in PrxI and persistence of neutrophil recruitment. In contrast, these changes did not occur in the Nrf2-deficient mice. These results demonstrate that Nrf2 regulates the inflammation process downstream of 15d-PGJ2 by orchestrating the recruitment of inflammatory cells and regulating the gene expression within those cells.

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The Impact of Neutrophil Recruitment to the Skin on the Pathology Induced by Leishmania Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.649348 ◽

2021 ◽

Vol 12 ◽

Author(s):

Katiuska Passelli ◽

Oaklyne Billion ◽

Fabienne Tacchini-Cottier

Keyword(s):

Clinical Manifestations ◽

Adaptive Immune Response ◽

Subsequent Development ◽

Inflammatory Cells ◽

Immune Defense ◽

Neutrophil Recruitment ◽

Sand Fly ◽

Leishmania Infection ◽

Infected Female ◽

The Impact

Leishmania (L.) are obligate intracellular protozoan parasites that cause the leishmaniases, a spectrum of neglected infectious vector-borne diseases with a broad range of clinical manifestations ranging from local cutaneous, to visceral forms of the diseases. The parasites are deposited in the mammalian skin during the blood meal of an infected female phlebotomine sand fly. The skin is a complex organ acting as the first line of physical and immune defense against pathogens. Insults to skin integrity, such as that occurring during insect feeding, induces the local secretion of pro-inflammatory molecules generating the rapid recruitment of neutrophils. At the site of infection, skin keratinocytes play a first role in host defense contributing to the recruitment of inflammatory cells to the infected dermis, of which neutrophils are the first recruited cells. Although neutrophils efficiently kill various pathogens including Leishmania, several Leishmania species have developed mechanisms to survive in these cells. In addition, through their rapid release of cytokines, neutrophils modulate the skin microenvironment at the site of infection, a process shaping the subsequent development of the adaptive immune response. Neutrophils may also be recruited later on in unhealing forms of cutaneous leishmaniasis and to the spleen and liver in visceral forms of the disease. Here, we will review the mechanisms involved in neutrophil recruitment to the skin following Leishmania infection focusing on the role of keratinocytes in this process. We will also discuss the distinct involvement of neutrophils in the outcome of leishmaniasis.

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Healing effects of curcumin nanoparticles in deep tissue injury mouse model.

Current Drug Delivery ◽

10.2174/1567201818666201214125237 ◽

2020 ◽

Vol 18 ◽

Author(s):

Zirui Zhang ◽

Shangcong Han ◽

Panpan Liu ◽

Xu Yang ◽

Jing Han ◽

...

Keyword(s):

Wound Healing ◽

Mrna Expression ◽

Tissue Injury ◽

Inflammatory Cells ◽

Pcr Analysis ◽

Protective Effects ◽

Deep Tissue ◽

Deep Tissue Injury

Background: Chronic inflammation and lack of angiogenesis are the important pathological mechanisms in deep tissue injury (DTI). Curcumin is a well-known anti-inflammatory and antioxidant agent. However, curcumin is unstable under acidic and alkaline conditions, and can be rapidly metabolized and excreted in the bile, which shortens its bioactivity and efficacy. Objective: This study aimed to prepare curcumin-loaded poly (lactic-co-glycolic acid) nanoparticles (CPNPs) and to elucidate the protective effects and underlying mechanisms of wound healing in DTI models. Methods: CPNPs were evaluated for particle size, biocompatibility, in vitro drug release and their effect on in vivo wound healing. Results : The results of in vivo wound closure analysis revealed that CPNP treatments significantly improved wound contraction rates (p<0.01) at a faster rate than other three treatment groups. H&E staining revealed that CPNP treatments resulted in complete epithelialization and thick granulation tissue formation, whereas control groups resulted in a lack of compact epithelialization and persistence of inflammatory cells within the wound sites. Quantitative real-time PCR analysis showed that treatment with CPNPs suppressed IL-6 and TNF-α mRNA expression, and up-regulated TGF-β, VEGF-A and IL-10 mRNA expression. Western blot analysis showed up-regulated protein expression of TGF-β, VEGF-A and phosphorylatedSTAT3. Conclusion: Our results showed that CPNPs enhanced wound healing in DTI models, through modulation of the JAK2/STAT3 signalling pathway and subsequent upregulation of pro-healing factors.

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Metagenomic Analysis of the Fecal Archaeome in Suckling Piglets Following Perinatal Tulathromycin Metaphylaxis

Animals ◽

10.3390/ani11061825 ◽

2021 ◽

Vol 11 (6) ◽

pp. 1825

Author(s):

Mohamed Zeineldin ◽

Ameer Megahed ◽

Benjamin Blair ◽

Brian Aldridge ◽

James Lowe

Keyword(s):

Sequencing Analysis ◽

Metagenomic Sequencing ◽

Post Intervention ◽

Gastrointestinal Microbiome ◽

Health And Wellbeing ◽

Suckling Piglets ◽

And Function ◽

Changes Over Time ◽

And Control ◽

The Impact

The gastrointestinal microbiome plays an important role in swine health and wellbeing, but the gut archaeome structure and function in swine remain largely unexplored. To date, no metagenomics-based analysis has been done to assess the impact of an early life antimicrobials intervention on the gut archaeome. The aim of this study was to investigate the effects of perinatal tulathromycin (TUL) administration on the fecal archaeome composition and diversity in suckling piglets using metagenomic sequencing analysis. Sixteen litters were administered one of two treatments (TUL; 2.5 mg/kg IM and control (CONT); saline 1cc IM) soon after birth. Deep fecal swabs were collected from all piglets on days 0 (prior to treatment), 5, and 20 post intervention. Each piglet’s fecal archaeome was composed of rich and diverse communities that showed significant changes over time during the suckling period. At the phylum level, 98.24% of the fecal archaeome across all samples belonged to Euryarchaeota. At the genus level, the predominant archaeal genera across all samples were Methanobrevibacter (43.31%), Methanosarcina (10.84%), Methanococcus (6.51%), and Methanocorpusculum (6.01%). The composition and diversity of the fecal archaeome between the TUL and CONT groups at the same time points were statistically insignificant. Our findings indicate that perinatal TUL metaphylaxis seems to have a minimal effect on the gut archaeome composition and diversity in sucking piglets. This study improves our current understanding of the fecal archaeome structure in sucking piglets and provides a rationale for future studies to decipher its role in and impact on host robustness during this critical phase of production.

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The Formation and Control of Ice Crystal and Its Impact on the Quality of Frozen Aquatic Products: A Review

Crystals ◽

10.3390/cryst11010068 ◽

2021 ◽

Vol 11 (1) ◽

pp. 68

Author(s):

Mingtang Tan ◽

Jun Mei ◽

Jing Xie

Keyword(s):

Product Quality ◽

Freezing Point ◽

Ice Crystals ◽

Affecting Factors ◽

Frozen Food ◽

Aquatic Products ◽

Size Number ◽

Underlying Mechanisms ◽

And Control ◽

Ice Crystallization

Although freezing has been used to delay the deterioration of product quality and extend its shelf life, the formation of ice crystals inevitably destroys product quality. This comprehensive review describes detailed information on the effects of ice crystals on aquatic products during freezing storage. The affecting factors (including nucleation temperature, freezing point, freezing rate, and temperature fluctuation) on the size, number, distribution, and shape of ice crystals are also elaborated in detail. Meanwhile, the corresponding technologies to control ice crystals have been developed based on these affecting factors to control the formation of ice crystals by inhibiting or inducing ice crystallization. In addition, the effects of ice crystals on the water, texture, and protein of aquatic products are comprehensively discussed, and the paper tries to describe their underlying mechanisms. This review can provide an understanding of ice crystallization in the aquatic products during freezing and contribute more clues for maintaining frozen food quality.

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Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

Biomedicines ◽

10.3390/biomedicines9040359 ◽

2021 ◽

Vol 9 (4) ◽

pp. 359

Author(s):

Hsiang-Hao Chuang ◽

Yen-Yi Zhen ◽

Yu-Chen Tsai ◽

Cheng-Hao Chuang ◽

Ming-Shyan Huang ◽

...

Keyword(s):

Cancer Therapy ◽

Tumor Suppressors ◽

Protein Conformation ◽

Genome Stability ◽

Recent Progress ◽

Multiple Roles ◽

Cancer Development ◽

Cancer Hallmarks ◽

Underlying Mechanisms ◽

And Function

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

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