An Interactive Network of Elastase, Secretases, and PAR-2 Protein Regulates CXCR1 Receptor Surface Expression on Neutrophils

Bakele, Martina; Lotz-Havla, Amelie S.; Jakowetz, Anja; Carevic, Melanie; Marcos, Verónica; Muntau, Ania C.; Gersting, Søren W.; Hartl, Dominik

doi:10.1074/jbc.m114.575803

Cited by 18 publications

(13 citation statements)

References 38 publications

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“…CXCR1 on neutrophils may also be downregulated in response to inflammatory agents such as TNF-α, Toll-like receptor 2 (TLR2) and TLR4 agonists, H. pylori and elastase or upon reoxygenation. [121][122][123][124][125] In addition, exposure to body fluids from patients with inflammatory pathologies induces a rapid downregulation of CXCR1 on healthy donor neutrophils. For example, reduced CXCR1 expression was observed in healthy donor neutrophils incubated with the plasma from patients with alcoholic hepatitis.…”

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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Section: C5ar1mentioning

confidence: 99%

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

2020

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“…NSPs also cleave and thereby either inactivate or activate receptors on several different cell types (see also ). More recent examples showed proteolytic inactivation of C5a receptors on myeloid cells and activation of protease‐activated receptors (PARs) on EC , neurons , and neutrophils . In the context of granulomatosis with polyangiitis (GPA), a ANCA‐associated vasculitis (AAV) form, it is interesting that enzymatically active PR3, via PAR‐2, induced maturation of monocyte‐derived immature DC.…”

Section: Nsps Actions Within and Outside The Neutrophil And Interactimentioning

confidence: 99%

Neutral serine proteases of neutrophils

Kettritz

2016

Immunological Reviews

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Neutrophil serine proteases (NSPs) exercise tissue-degrading and microbial-killing effects. The spectrum of NSP-mediated functions grows continuously, not least because of methodological progress. Sensitive and specific FRET substrates were developed to study the proteolytic activity of each NSP member. Advanced biochemical methods are beginning to characterize common and specific NSP substrates. The resulting novel information indicates that NSPs contribute not only to genuine inflammatory neutrophil functions but also to autoimmunity, metabolic conditions, and cancer. Tight regulatory mechanisms control the proteolytic potential of NSPs. However, not all NSP functions depend on their enzymatic activity. Proteinase-3 (PR3) is somewhat unique among the NSPs for PR3 functions as an autoantigen. Patients with small-vessel vasculitis develop autoantibodies to PR3 that bind their target antigens on the neutrophil surface and trigger neutrophil activation. These activated cells subsequently contribute to vascular necrosis with life-threatening multiorgan failure. This article discusses various aspects of NSP biology and highlights translational aspects with strong clinical implications.

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“…IL-8 not only is responsible for leukocyte recruitment but also might trigger EndMT and increase the survival and proliferation of endothelial-derived fibroblasts/myofibroblasts, leading to fibrosis [ 6 , 63 ]. Additionally, elastase is also believed to cleave the IL-8 receptor CXCR1, interfering with neutrophil functions and antibacterial abilities, thereby prolonging inflammation, which in turn increases additional fibrosis-based changes [ 64 ]. Prolonged inflammation might also occur through the elastase-mediated degradation of complement, releasing the strong neutrophil chemoattractant, C5a [ 65 ].…”

Section: Leukocytes In Fibrosis: Unanswered Questionsmentioning

confidence: 99%

Leukocytes: The Double‐Edged Sword in Fibrosis

Kryczka

Boncela

2015

Mediators of Inflammation

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Skin tissue scar formation and fibrosis are often characterized by the increased production and deposition of extracellular matrix components, accompanied by the accumulation of a vast number of myofibroblasts. Scaring is strongly associated with inflammation and wound healing to regain tissue integrity in response to skin tissue injury. However, increased and uncontrolled inflammation, repetitive injury, and individual predisposition might lead to fibrosis, a severe disorder resulting in the formation of dense and stiff tissue that loses the physical properties and physiological functions of normal tissue. Fibrosis is an extremely complicated and multistage process in which bone marrow-derived leukocytes act as both pro- and antifibrotic agents, and therefore, few, if any, effective therapies are available for the most severe and lethal forms of fibrosis. Herein, we discuss the current knowledge on the multidimensional impact of leukocytes on the induction of fibrosis, focusing on skin fibrosis.

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An Interactive Network of Elastase, Secretases, and PAR-2 Protein Regulates CXCR1 Receptor Surface Expression on Neutrophils

Cited by 18 publications

References 38 publications

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

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

Neutral serine proteases of neutrophils

Leukocytes: The Double‐Edged Sword in Fibrosis

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