Neutrophil-Derived Cathelicidin Promotes Adhesion of Classical Monocytes

Wantha, Sarawuth; Alard, Jean-Eric; Megens, Remco T. A.; Does, Anne M. van der; Döring, Yvonne; Drechsler, Maik; Pham, Christine; Wang, Mingwei; Wang, Jimin; Gallo, Richard L.; Hundelshausen, Philipp von; Lindbom, Lennart; Hackeng, Tilman M.; Weber, Christian; Soehnlein, Oliver

doi:10.1161/circresaha.112.300666

Cited by 138 publications

(118 citation statements)

References 53 publications

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“…It is plausible that CCR2 independent pathways might be altered. Relevantly, LXA 4 can promote nonphlogistic monocyte migration (31), and the same occurs for another Fpr2/3 ligand, the cathelicidin LL-37 (32).…”

Section: Discussionmentioning

confidence: 88%

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

Gobbetti

Coldewey

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

104

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Significance Sepsis defines a syndrome with poor clinical management characterized by overlapping phases of excessive inflammation temporally aligned with an immunosuppressed state. We define an endogenous pathway centered on formyl-peptide receptor 2/3 (Fpr2/3)—ortholog to human FPR2/ALX (receptor for lipoxin A4)—that protects the host against polymicrobial sepsis. Using null mice and proof-of-concept experiments with a peptide–agonist, we demonstrate how engagement of Fpr2/3 is crucial to enact nonredundant functions that span from control of cell recruitment and phagocytosis, modulation of soluble mediator generation, to containment of bacteremia, thus preventing spreading to vital organs and opening new opportunities to manipulate the host response in sepsis.

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Section: Discussionmentioning

confidence: 88%

Nonredundant protective properties of FPR2/ALX in polymicrobial murine sepsis

Gobbetti

Coldewey

Chen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

104

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“…For example, acute-phase protein serum amyloid A and cathelicidin mediate FPR2-dependent proinflammatory leukocyte activation, including leukocyte trafficking, cytokine secretion, and inhibition of neutrophil apoptosis. [34][35][36] In contrast, AnxA1, Ac2-26, and lipoxin A4 also signal through FPR2 to inhibit leukocyte recruitment, enhance neutrophil apoptosis, and macrophage efferocytosis, 35,37 key events in inflammatory resolution. Lipid and peptide ligands act with different affinities and bind to distinct pockets on the receptor, thus making a direct competition unlikely.…”

Section: Apoe -/-+ αCxcr2mentioning

confidence: 99%

Annexin A1 Counteracts Chemokine-Induced Arterial Myeloid Cell Recruitment

Drechsler¹,

Jong²,

Rossaint³

et al. 2015

Circulation Research

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128

123

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Rationale: Chemokine-controlled arterial leukocyte recruitment is a crucial process in atherosclerosis. Formyl peptide receptor 2 (FPR2) is a chemoattractant receptor that recognizes proinflammatory and proresolving ligands. The contribution of FPR2 and its proresolving ligand annexin A1 to atherosclerotic lesion formation is largely undefined. Objective: Because of the ambivalence of FPR2 ligands, we here investigate the role of FPR2 and its resolving ligand annexin A1 in atherogenesis. Methods and Results: Deletion of FPR2 or its ligand annexin A1 enhances atherosclerotic lesion formation, arterial myeloid cell adhesion, and recruitment. Mechanistically, we identify annexin A1 as an endogenous inhibitor of integrin activation evoked by the chemokines CCL5, CCL2, and CXCL1. Specifically, the annexin A1 fragment Ac2-26 counteracts conformational activation and clustering of integrins on myeloid cells evoked by CCL5, CCL2, and CXCL1 through inhibiting activation of the small GTPase Rap1. In vivo administration of Ac2-26 largely diminishes arterial recruitment of myeloid cells in a FPR2-dependent fashion. This effect is also observed in the presence of selective antagonists to CCR5, CCR2, or CXCR2, whereas Ac2-26 was without effect when all 3 chemokine receptors were antagonized simultaneously. Finally, repeated treatment with Ac2-26 reduces atherosclerotic lesion sizes and lesional macrophage accumulation. Conclusions: Instructing the annexin A1-FPR2 axis harbors a novel approach to target arterial leukocyte recruitment. With the ability of Ac2-26 to counteract integrin activation exerted by various chemokines, delivery of Ac2-26 may be superior in inhibition of arterial leukocyte recruitment when compared with blocking individual chemokine receptors.

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“…Neutrophils are excellent chaperone candidates because they are among the first to respond and because they contain large quantities of preformed granular proteins. 6 In this issue of Circulation Research, 7 Wantha and colleagues provide mechanistic detail as to how extravasated neutrophils may be alerting monocytes.…”

Section: Article See P 792mentioning

confidence: 99%