Endotoxin promotes neutrophil hierarchical chemotaxis via the p38-membrane receptor pathway

Xu, Wei; Qin, Weiting; Zhang, Yisen; Zhang, Huafeng; Sun, Bo

doi:10.18632/oncotarget.12093

Cited by 13 publications

(15 citation statements)

References 34 publications

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“…Endotoxin was recently shown to impair neutrophil chemotaxis toward CXCL8 and hence the “prioritization” process of fMLP via a p38‐dependent mechanism. Thus, the elevated levels of p38 phosphorylation found on RC‐treated neutrophils could promote similar signaling inhibitory effects on CXCL8‐induced migration . Cell tracking data corroborates this hypothesis, as seen by changes in directionality to necrotic zones and distance traveled after RC.…”

Section: Discussionsupporting

confidence: 65%

GRPR antagonist protects from drug‐induced liver injury by impairing neutrophil chemotaxis and motility

Czepielewski¹,

Jaeger²,

Marques

et al. 2017

Eur J Immunol

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Drug-induced liver injury (DILI) is a major cause of acute liver failure (ALF), where hepatocyte necrotic products trigger liver inflammation, release of CXC chemokine receptor 2 (CXCR2) ligands (IL-8) and other neutrophil chemotactic molecules. Liver infiltration by neutrophils is a major cause of the life-threatening tissue damage that ensues. A GRPR (gastrin-releasing peptide receptor) antagonist impairs IL-8-induced neutrophil chemotaxis in vitro. We investigated its potential to reduce acetaminophen-induced ALF, neutrophil migration, and mechanisms underlying this phenomenon. We found that acetaminophen-overdosed mice treated with GRPR antagonist had reduced DILI and neutrophil infiltration in the liver. Intravital imaging and cell tracking analysis revealed reduced neutrophil mobility within the liver. Surprisingly, GRPR antagonist inhibited CXCL2-induced migration in vivo, decreasing neutrophil activation through CD11b and CD62L modulation. Additionally, this compound decreased CXCL8-driven neutrophil chemotaxis in vitro independently of CXCR2 internalization, induced activation of MAPKs (p38 and ERK1/2) and downregulation of neutrophil adhesion molecules CD11b and CD66b. In silico analysis revealed direct binding of GRPR antagonist and CXCL8 to the same binding spot in CXCR2. These findings indicate a new potential use for GRPR antagonist for treatment of DILI through a mechanism involving adhesion molecule modulation and possible direct binding to CXCR2.

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Section: Discussionsupporting

confidence: 65%

GRPR antagonist protects from drug‐induced liver injury by impairing neutrophil chemotaxis and motility

Czepielewski¹,

Jaeger²,

Marques

et al. 2017

Eur J Immunol

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“…LPS-triggered activation of p38 MAPKs is a critical signal transduction pathway that modulates various neutrophil functions (28,29). In the present study, we demonstrated that AMP inhibited the phosphorylation of p38 MAPK in LPS-activated neutrophils.…”

Section: Discussionsupporting

confidence: 61%

Extracellular AMP Suppresses Endotoxemia-Induced Inflammation by Alleviating Neutrophil Activation

et al. 2020

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Intracellular adenosine monophosphate (AMP) is indispensable for cellular metabolic processes, and it is interconverted to ADP and/or ATP or activates AMP-activated protein kinase (AMPK). However, the specific biological function of extracellular AMP has not been identified. We evaluated the effect of extracellular AMP using in vivo and in vitro models of endotoxemia. We found that AMP inhibited inflammation and neutrophil activation in lipopolysaccharide (LPS)-induced endotoxemic mice. The effects of extracellular AMP were abolished by an adenosine 1 receptor (A1R) antagonist but were not influenced by inhibiting the conversion of AMP to adenosine (ADO), indicating that AMP inhibited inflammation by directly activating A1R. In addition, in vitro experiments using LPS-stimulated mouse neutrophils showed that AMP inhibited LPS-induced reactive oxygen species (ROS) production, degranulation, and cytokine production, while the effects were reversed by an A1R antagonist. Further research showed that AMP regulated LPS-stimulated neutrophil functions by inhibiting the p38 MAPK pathway. These findings were also confirmed in primary neutrophils derived from healthy human blood. Moreover, we collected serum samples from septic patients. We found that AMP levels were increased compared with those of healthy volunteers and that AMP levels were negatively correlated with disease severity. Together, these data provide evidence that extracellular AMP acts on A1R to suppress endotoxemia-induced inflammation by inhibiting neutrophil overactivation and that the p38 MAPK signaling pathway is involved.

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“…Regarding the chemotaxis of human neutrophils, fMLF-induced migration predominates over CXCL8or LTB 4 -induced chemotactic cues in vitro. 89 This superior potency of fMLF is enhanced in the presence of LPS, which increases FPR1 expression while inducing internalization of CXCR1/2, BLT1 and C5aR1. 90 In contrast to LPS, IL-4 inhibits the expression of FPR1 on neutrophils.…”

Section: C5ar1mentioning

confidence: 99%

Neutrophil chemoattractant receptors in health and disease: double-edged swords

2020

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Neutrophils are frontline cells of the innate immune system. These effector leukocytes are equipped with intriguing antimicrobial machinery and consequently display high cytotoxic potential. Accurate neutrophil recruitment is essential to combat microbes and to restore homeostasis, for inflammation modulation and resolution, wound healing and tissue repair. After fulfilling the appropriate effector functions, however, dampening neutrophil activation and infiltration is crucial to prevent damage to the host. In humans, chemoattractant molecules can be categorized into four biochemical families, i.e., chemotactic lipids, formyl peptides, complement anaphylatoxins and chemokines. They are critically involved in the tight regulation of neutrophil bone marrow storage and egress and in spatial and temporal neutrophil trafficking between organs. Chemoattractants function by activating dedicated heptahelical G protein-coupled receptors (GPCRs). In addition, emerging evidence suggests an important role for atypical chemoattractant receptors (ACKRs) that do not couple to G proteins in fine-tuning neutrophil migratory and functional responses. The expression levels of chemoattractant receptors are dependent on the level of neutrophil maturation and state of activation, with a pivotal modulatory role for the (inflammatory) environment. Here, we provide an overview of chemoattractant receptors expressed by neutrophils in health and disease. Depending on the (patho)physiological context, specific chemoattractant receptors may be up-or downregulated on distinct neutrophil subsets with beneficial or detrimental consequences, thus opening new windows for the identification of disease biomarkers and potential drug targets.

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Endotoxin promotes neutrophil hierarchical chemotaxis via the p38-membrane receptor pathway

Cited by 13 publications

References 34 publications

GRPR antagonist protects from drug‐induced liver injury by impairing neutrophil chemotaxis and motility

GRPR antagonist protects from drug‐induced liver injury by impairing neutrophil chemotaxis and motility

Extracellular AMP Suppresses Endotoxemia-Induced Inflammation by Alleviating Neutrophil Activation

Neutrophil chemoattractant receptors in health and disease: double-edged swords

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