The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia

Machado, Marina Amaral de Ávila; Tavares, Luciana P.; Souza, Geovanna V. Santos; Queiroz-Júnior, Celso Martins; Ascenção, Fernando R.; Lopes, Mateus Eustáquio; Garcia, Cristiana C.; Menezes, Gustavo B.; Perretti, Mauro; Russo, Remo Castro; Teixeira, Mauro Martins; Sousa, Lirlândia P.

doi:10.1096/fj.201902172r

Cited by 62 publications

(66 citation statements)

References 55 publications

(139 reference statements)

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“…The following day BMDMs were stimulated with the TLR4 agonist lipopolysaccharide (LPS; from Escherichia coli serotype O:111:B4; 1 μg/ml; Sigma‐Aldrich) for 1 hr as previously described, 23 or stimulated with the TLR2 agonist lipoteichoic acid (LTA; 10 μg/ml; Sigma‐Aldrich) 32 . The AnxA1 peptidomimetic Ac2‐26 (32 μ m; GeneScript) 33 and a selective FPR2 antagonist, WRW4 (10 μ m; Calbiochem) 34 were added into the cells prior to inflammasome activation. Then BMDMs were stimulated with inflammasome activators in RPMI 1640 medium without FBS: MSU crystals (300 μg/ml for 6 hr); 29 Silica (250 μg/ml for 6 hr); 35 adenosine 5′‐triphosphate disodium salt (ATP 5 m m for 30 min); 36 Poly(dA:dT) (Sigma‐Aldrich; 500 ng/ml for 2 hr); 37 Legionella pneumophila bacteria (strain JR32 – MOI of 10 for 4 hr) 37 .…”

Section: Methodsmentioning

confidence: 99%

The role of annexin A1 in the modulation of the NLRP3 inflammasome

Galvão¹,

Carvalho²,

Vago³

et al. 2020

Immunology

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Annexins are well-known Ca 2+ phospholipid-binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti-inflammatory and proresolving properties through its binding to the formyl-peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)-1b release in response to activators of the nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL-1b release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL-1b, NLRP3 and caspase-1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co-localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti-inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2-independent manner.Bone marrow-derived macrophages (BMDMs) were obtained as previously described. 31 Briefly, bone marrow cells were collected from femurs of wild-type (WT), AnxA1 À/À and FPR2/3 À/À mice and differentiated for 7 days in RPMI 1640 supplemented with 20% of fetal bovine serum (FBS) and 30% L929 conditioned medium.

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Section: Methodsmentioning

confidence: 99%

The role of annexin A1 in the modulation of the NLRP3 inflammasome

Galvão¹,

Carvalho²,

Vago³

et al. 2020

Immunology

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“…In a recent study it has been shown that Ac2-26 reduces the inflammatory response and bacterial loads after pneumococcal pneumonia, and that this protective effect is mediated via FPR2 (43). Interestingly, in that study it was observed that FPR2-deficiency results in higher levels of the pro-inflammatory cytokines compared to WT littermates (43). In our study, we observed higher Tnfα, Ccl3 and Cxcl10 mRNA expression levels in infected Fpr2 −/− compared to WT mice (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…Lower neutrophil counts in the CNS of Ac2-26-treated meningitis mice might principally be due to a stimulation of bacterial phagocytosis by Ac2-26 in the periphery (43). To verify or falsify this assumption, we measured in parallel the bacterial load in the peripheral circulation (i.e.…”

Section: Discussionmentioning

confidence: 99%

“…With respect to Ac2-26 it has been shown that Ac2-26 inhibits the adhesion and transmigration of leukocytes, thus limiting the intensity and duration of the inflammatory response and supporting the proliferation and immigration of epithelial cells (16,17). For Ac2-26 and Annexin A1, an anti-inflammatory effect was shown in multiple sclerosis, pneumococcal pneumonia, arthritis and uveitis as well as during wound healing (18)(19)(20). body weight) and infected with the Streptococcus pneumoniae D39 (type 2) strain (10 4 colony-forming units/ml).…”

Section: Introductionmentioning

confidence: 99%

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Formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis

Rüger

Kipp

Schubert

et al. 2020

Preprint

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BackgroundBacterial meningitis is, despite progress in research and the development of new treatment strategies, still a cause of severe neurological disability. The brain is protected from penetrating pathogens by the blood-brain barrier and the innate immune system. The invading pathogens are recognized by pattern recognition receptors including the G-protein coupled formyl peptide receptors (FPRs), which are expressed by immune cells of the central nervous system. FPRs show a broad spectrum of ligands including pro- and anti-inflammatory ones. Here, we investigated the effects of the AnnexinA1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis.MethodsWildtype (WT), Fpr1 and Fpr2-deficient mice were intrathecally infected with Streptococcus pneumoniae D39 (type 2). Subsequently, the different mice groups were treated by intraperitoneal injections of Ac2-26 (1 mg/kg body weight) 2, 8 and 24 hour after the infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time RT-PCR 30 h after infection.ResultsAc2-26 treated mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glia cell responses. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice.ConclusionsEven with appropriate antimicrobial therapy, mortality during bacterial meningitis is high and so attention has recently focused on adjunctive therapies. Our results suggest that Ac2-26 might be a novel adjunctive therapy for Streptococcus pneumoniae-induced meningitis.* The two last authors contributed equally to this study.

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“…Moreover, the pathogenetic involvement of these molecules qualifies them as relevant drug targets or therapeutics as well. Indeed, accumulating preclinical data have encouraged envisaging DAMPs as therapeutic targets for inhibition [5,[12][13][14][15][16][17] and administration of SAMPs as candidate drugs [5,[18][19][20][21][22][23][24][25][26][27] for treating acute or chronic inflammatory disorders. On the other hand, DAMPs may also be…”

Section: Introductionmentioning

confidence: 99%

Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics: A Note of Caution

Land

2020

Mol Diagn Ther

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This opinion article discusses the increasing attention paid to the role of activating damage-associated molecular patterns (DAMPs) in initiation of inflammatory diseases and suppressing/inhibiting DAMPs (SAMPs) in resolution of inflammatory diseases and, consequently, to the future roles of these novel biomarkers as therapeutic targets and therapeutics. Since controlled production of DAMPs and SAMPs is needed to achieve full homeostatic restoration and repair from tissue injury, only their pathological, not their homeostatic, concentrations should be therapeutically tackled. Therefore, distinct caveats are proposed regarding choosing DAMPs and SAMPs for therapeutic purposes. For example, we discuss the need to a priori identify and define a context-dependent "homeostatic DAMP:SAMP ratio" in each case and a "homeostatic window" of DAMP and SAMP concentrations to guarantee a safe treatment modality to patients. Finally, a few clinical examples of how DAMPs and SAMPs might be used as therapeutic targets or therapeutics in the future are discussed, including inhibition of DAMPs in hyperinflammatory processes (e.g., systemic inflammatory response syndrome, as currently observed in , administration of SAMPs in chronic inflammatory diseases, inhibition of SAMPs in hyperresolving processes (e.g., compensatory antiinflammatory response syndrome), and administration/induction of DAMPs in vaccination procedures and anti-cancer therapy.

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The Annexin A1/FPR2 pathway controls the inflammatory response and bacterial dissemination in experimental pneumococcal pneumonia

Cited by 62 publications

References 55 publications

The role of annexin A1 in the modulation of the NLRP3 inflammasome

The role of annexin A1 in the modulation of the NLRP3 inflammasome

Formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis

Use of DAMPs and SAMPs as Therapeutic Targets or Therapeutics: A Note of Caution

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