A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide

Önnheim, Karin; Christenson, Karin; Gabl, Michael; Burbiel, Joachim C.; Müller, Christian; Oprea, Tudor I.; Bylund, Johan; Dahlgren, Cláes; Forsman, Huamei

doi:10.1016/j.yexcr.2014.01.023

Cited by 47 publications

(60 citation statements)

References 51 publications

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“…The results showing weak stimulatory effect of the NADPH-oxidase in resting cells exerted by CFP-10 but a potent effect on cells with a disrupted cytoskeleton are similar to those showing the neutrophil response seen in the presence of several other neutrophil chemoattractant GPCRs (32,48). The CFP-10 receptor differs from the FPRs in that NADPH-oxidase activation through the receptor requires prior disruption of the actin cytoskeleton, an observation that is likely explained by the presence of different signaling pathways leading from receptor binding to activation of the NADPH-oxidase, in addition to differences in receptor coupling to the actin cytoskeleton (29,32,49).…”

Section: Discussionsupporting

confidence: 52%

CFP-10 from Mycobacterium tuberculosis Selectively Activates Human Neutrophils through a Pertussis Toxin-Sensitive Chemotactic Receptor

et al. 2015

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cUpon infection with Mycobacterium tuberculosis, neutrophils are massively recruited to the lungs, but the role of these cells in combating the infection is poorly understood. Through a type VII secretion system, M. tuberculosis releases a heterodimeric protein complex, containing a 6-kDa early secreted antigenic target (ESAT-6) and a 10-kDa culture filtrate protein (CFP-10), that is essential for virulence. Whereas the ESAT-6 component possesses multiple virulence-related activities, no direct biological activity of CFP-10 has been shown, and CFP-10 has been described as a chaperone protein for ESAT-6. We here show that the ESAT-6:CFP-10 complex induces a transient release of Ca 2؉ from intracellular stores in human neutrophils. Surprisingly, CFP-10 rather than ESAT-6 was responsible for triggering the Ca 2؉ response, in a pertussis toxin-sensitive manner, suggesting the involvement of a G-protein-coupled receptor. In line with this, the response was accompanied by neutrophil chemotaxis and activation of the superoxide-producing NADPH-oxidase. Neutrophils were unique among leukocytes in responding to CFP-10, as monocytes and lymphocytes failed to produce a Ca 2؉ signal upon stimulation with the M. tuberculosis protein. Hence, CFP-10 may contribute specifically to neutrophil recruitment and activation during M. tuberculosis infection, representing a novel biological role for CFP-10 in the ESAT-6:CFP-10 complex, beyond the previously described chaperone function.

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Section: Discussionsupporting

confidence: 52%

CFP-10 from Mycobacterium tuberculosis Selectively Activates Human Neutrophils through a Pertussis Toxin-Sensitive Chemotactic Receptor

et al. 2015

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“…The molecular basis for this reactivation is an inhibition of the coupling of ligand-receptor complexes to the actin cytoskeleton, an interaction that normally terminates the response and desensitizes the receptors (30,31). Recently, we described another, more physiological mode of FPR1 and FPR2 reactivation, involving receptor cross-talk with P2Y 2 R and PAFRs upon stimulation with the receptor-specific agonists ATP and PAF, respectively (32,33). The signals involved in this type of receptor cross-talk have not yet been identified.…”

Section: F2m2 Triggers a Pertussis Toxin-sensitive Response And Does mentioning

confidence: 99%

The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase

Holdfeldt

Skovbakke

Winther

et al. 2016

Journal of Biological Chemistry

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Neutrophils expressing formyl peptide receptor 2 (FPR2) play key roles in host defense, immune regulation, and resolution of inflammation. Consequently, the search for FPR2-specific modulators has attracted much attention due to its therapeutic potential. Earlier described agonists for this receptor display potent activity for the human receptor (FPR2) but low activity for the mouse receptor orthologue (Fpr2), rendering them inapplicable in murine models of human disease. Here we describe a novel FPR2 agonist, the proteolytically stable ␣-peptide/␤-pep- The molecular basis for directional neutrophil migration toward inflammatory sites is their ability to sense "danger signals" produced by microorganisms (i.e. pathogen-associated molecular patterns) and damaged host cells or tissues (i.e. damage-associated molecular patterns) (1). Human neutrophils express two members of the formyl peptide receptor family (FPR1 3 and FPR2), belonging to the family of G-protein-coupled receptors (GPCRs), which recognize pathogen-associated molecular patterns in the form of peptides with an N-terminal formyl-methionine residue, originating from bacterial (and mitochondrial) protein synthesis (2, 3). In addition, human neutrophils express GPCRs that recognize endogenous chemoattractants and damage-associated molecular patterns, including the split product of complement component C5 (C5a, recognized by C5aR), leukotriene LTB 4 (recognized by BLT1), the chemokine IL-8 (CXCL8, recognized by CXCR1 and CXCR2), platelet-activating factor (PAF, recognized by PAFR), and the nucleotide ATP (recognized by P2Y 2 R) (4, 5). Although the two human neutrophil FPRs, FPR1 and FPR2, display significant sequence similarity, they have distinct, albeit partially overlapping, ligand recognition profiles (2, 6, 7).The mouse genome contains at least eight mouse Fprs, among which Fpr1 and Fpr2 are regarded as the orthologues of the receptors expressed in human neutrophils (8, 9). Studies using mice deficient in Fpr1 or Fpr2 have demonstrated roles of these receptors not only in host defense but also in immune regulation and in the resolution of inflammation (10 -12). The therapeutic potential of targeting these receptors in inflammatory/infectious conditions, such as atherosclerosis, cancer, neurodegenerative diseases, and sepsis (see a recent review (13)), justifies the search for receptor-specific ligands that can function as agonists, antagonists, or allosteric modulators. However, a direct translation of knowledge between humans and

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“…Activation of neutrophils through FPRs induces a variety of pro-inflammatory and antibacterial effector mechanisms including production of ROS, and release of antimicrobial peptides (AMPs) and hydrolytic enzymes from intracellular granules [20]. Furthermore, FPRs regulate the inflammatory reactions in neutrophils by modulating signaling through many other receptors in a process termed receptor cross-talk [21][22][23][24]. The role of FPRs in regulation of inflammation is highlighted by their suggested involvement in both systemic [25] and local [26][27][28] inflammatory responses.…”

Section: Of 52mentioning

confidence: 99%

The proteolytically stable peptidomimetic Pam-(Lys-βNSpe)6-NH2 selectively inhibits human neutrophil activation via formyl peptide receptor 2

Skovbakke

Heegaard

Larsen

et al. 2015

Biochemical Pharmacology

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A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide

Cited by 47 publications

References 51 publications

CFP-10 from Mycobacterium tuberculosis Selectively Activates Human Neutrophils through a Pertussis Toxin-Sensitive Chemotactic Receptor

CFP-10 from Mycobacterium tuberculosis Selectively Activates Human Neutrophils through a Pertussis Toxin-Sensitive Chemotactic Receptor

The Lipidated Peptidomimetic Lau-((S)-Aoc)-(Lys-βNphe)6-NH2 Is a Novel Formyl Peptide Receptor 2 Agonist That Activates Both Human and Mouse Neutrophil NADPH Oxidase

The proteolytically stable peptidomimetic Pam-(Lys-βNSpe)6-NH2 selectively inhibits human neutrophil activation via formyl peptide receptor 2

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