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

Abstract 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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The formyl peptide receptor agonist Ac2-26 alleviates neuroinflammation in a mouse model of pneumococcal meningitis

Journal of Neuroinflammation ◽

10.1186/s12974-020-02006-w ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Marvin Rüger ◽

Eugenia Kipp ◽

Nadine Schubert ◽

Nicole Schröder ◽

Thomas Pufe ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Bacterial Meningitis ◽

Mouse Model ◽

Post Infection ◽

Pneumococcal Meningitis ◽

Hippocampal Formation ◽

Formyl Peptide Receptor ◽

Formyl Peptide ◽

Anti Inflammatory ◽

Deficient Mice

Abstract Background Bacterial meningitis is 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 annexin A1 mimetic peptide Ac2-26 in a mouse model of pneumococcal meningitis. Methods Wildtype (WT) and 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 h post-infection. The extent of inflammation was analyzed in various brain regions by means of immunohistochemistry and real-time reverse transcription polymerase chain reaction (RT-PCR) 30 h post-infection. Results Ac2-26-treated WT mice showed less severe neutrophil infiltration, paralleled by a reduced induction of pro-inflammatory glial cell responses in the hippocampal formation and cortex. While meningitis was ameliorated in Ac2-26-treated Fpr1-deficient mice, this protective effect was not observed in Fpr2-deficient mice. Irrespective of Ac2-26 treatment, inflammation was more severe in Fpr2-deficient compared to Fpr1-deficient mice. Conclusions In summary, this study demonstrates anti-inflammatory properties of Ac2-26 in a model of bacterial meningitis, which are mediated via FPR2, but not FPR1. Ac2-26 and other FPR2 modulators might be promising targets for the development of novel therapies for Streptococcus pneumoniae-induced meningitis.

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The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

Clinical Science ◽

10.1042/cs20140683 ◽

2015 ◽

Vol 128 (12) ◽

pp. 839-861 ◽

Cited By ~ 131

Author(s):

Dionne E.M. Maessen ◽

Coen D.A. Stehouwer ◽

Casper G. Schalkwijk

Keyword(s):

Advanced Glycation Endproducts ◽

Treatment Strategies ◽

Glyoxalase System ◽

Dicarbonyl Compound ◽

Glycation Endproducts ◽

Age Related ◽

Key Enzyme ◽

The Central Nervous System ◽

New Treatment

The formation and accumulation of advanced glycation endproducts (AGEs) are related to diabetes and other age-related diseases. Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is the major precursor in the formation of AGEs. MGO is mainly formed as a byproduct of glycolysis. Under physiological circumstances, MGO is detoxified by the glyoxalase system into D-lactate, with glyoxalase I (GLO1) as the key enzyme in the anti-glycation defence. New insights indicate that increased levels of MGO and the major MGO-derived AGE, methylglyoxal-derived hydroimidazolone 1 (MG-H1), and dysfunctioning of the glyoxalase system are linked to several age-related health problems, such as diabetes, cardiovascular disease, cancer and disorders of the central nervous system. The present review summarizes the mechanisms through which MGO is formed, its detoxification by the glyoxalase system and its effect on biochemical pathways in relation to the development of age-related diseases. Although several scavengers of MGO have been developed over the years, therapies to treat MGO-associated complications are not yet available for application in clinical practice. Small bioactive inducers of GLO1 can potentially form the basis for new treatment strategies for age-related disorders in which MGO plays a pivotal role.

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Progress in the Application of Drugs for the Treatment of Multiple Sclerosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.724718 ◽

2021 ◽

Vol 12 ◽

Author(s):

Weipeng Wei ◽

Denglei Ma ◽

Lin Li ◽

Lan Zhang

Keyword(s):

Multiple Sclerosis ◽

Demyelinating Disease ◽

Treatment Strategies ◽

New Drugs ◽

Focal Lesion ◽

Disease Modifying Drugs ◽

Physical Disorders ◽

The Central Nervous System ◽

Control Disease ◽

New Treatment

Multiple sclerosis (MS) is an autoimmune and chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesion in CNS and cause physical disorders. Although environmental factors and susceptibility genes are reported to play a role in the pathogenesis of MS, its etiology still remains unclear. At present, there is no complete cure, but there are drugs that decelerate the progression of MS. Traditional therapies are disease-modifying drugs that control disease severity. MS drugs that are currently marketed mainly aim at the immune system; however, increasing attention is being paid to the development of new treatment strategies targeting the CNS. Further, the number of neuroprotective drugs is presently undergoing clinical trials and may prove useful for the improvement of neuronal function and survival. In this review, we have summarized the recent application of drugs used in MS treatment, mainly introducing new drugs with immunomodulatory, neuroprotective, or regenerative properties and their possible treatment strategies for MS. Additionally, we have presented Food and Drug Administration-approved MS treatment drugs and their administration methods, mechanisms of action, safety, and effectiveness, thereby evaluating their treatment efficacy.

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Fpr2/CXCL1/2 Controls Rapid Neutrophil Infiltration to Inhibit Streptococcus agalactiae Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.786602 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zeyu Sun ◽

Wenhua Huang ◽

Yuling Zheng ◽

Peng Liu ◽

Wenbo Yang ◽

...

Keyword(s):

Streptococcus Agalactiae ◽

Group B Streptococcus ◽

Neutrophil Infiltration ◽

Immune Defense ◽

Formyl Peptide Receptor ◽

Signal Molecules ◽

Luminex Assay ◽

Risk Of Death ◽

Formyl Peptide ◽

Group B

Streptococcus agalactiae, also known as group B streptococcus (GBS), can cause pneumonia, meningitis, and bacteremia, making it a pathogen that can increase the risk of death in newborns and immunodeficient individuals. Neutrophils are the first barrier to a host’s innate immune defense against these infections. Fpr2(Formyl peptide receptor 2) is an important chemotactic receptor of neutrophils, though its activation would cause pro- and anti-inflammatory effects. In this study, we found that mice without Fpr2 receptor were highly susceptible to GBS infections. These mice demonstrated decreased chemotaxis to neutrophils, decreased bactericidal ability of neutrophils, and high mortality. RNA-seq and Luminex assay indicated that Fpr2 activates key signal molecules downstream and produces chemokines CXCL1/2 to chemotaxis neutrophils. Like Fpr2-/-, CXCL1/2 or neutrophil depletion impairs host’s ability to defend against GBS infection. Altogether, these data indicate that Fpr2 contributes to a host’s ability to control GBS infection and that a lack of Fpr2 was associated with selective impairment during the production of chemokines CXCL1 and CXCL2 as well as neutrophil recruitment. Here, We clarified that Fpr2, as a chemotactic receptor, could not only directly chemotactic neutrophils, but also regulate the production of chemokines to control infection by chemotactic neutrophils.

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The Contribution of Formyl Peptide Receptor Dysfunction to the Course of Neuroinflammation: A Potential Role in the Brain Pathology

Current Neuropharmacology ◽

10.2174/1570159x17666191019170244 ◽

2020 ◽

Vol 18 (3) ◽

pp. 229-249 ◽

Cited By ~ 2

Author(s):

Ewa Trojan ◽

Natalia Bryniarska ◽

Monika Leśkiewicz ◽

Magdalena Regulska ◽

Katarzyna Chamera ◽

...

Keyword(s):

Potential Role ◽

Membrane Receptors ◽

Formyl Peptide Receptor ◽

Proinflammatory Response ◽

Formyl Peptide ◽

Inflammatory Processes ◽

The Central Nervous System ◽

G Protein Coupled ◽

The Brain

: Chronic inflammatory processes within the central nervous system (CNS) are in part responsible for the development of neurodegenerative and psychiatric diseases. These processes are associated with, among other things, the increased and disturbed activation of microglia and the elevated production of proinflammatory factors. Recent studies indicated that the disruption of the process of resolution of inflammation (RoI) may be the cause of CNS disorders. It is shown that the RoI is regulated by endogenous molecules called specialized pro-resolving mediators (SPMs), which interact with specific membrane receptors. Some SPMs activate formyl peptide receptors (FPRs), which belong to the family of seven-transmembrane G protein-coupled receptors. These receptors take part not only in the proinflammatory response but also in the resolution of the inflammation process. Therefore, the activation of FPRs might have complex consequences. : This review discusses the potential role of FPRs, and in particular the role of FPR2 subtype, in the brain under physiological and pathological conditions and their involvement in processes underlying neurodegenerative and psychiatric disorders as well as ischemia, the pathogenesis of which involves the dysfunction of inflammatory processes.

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Corticotropin-Releasing Hormone Deficiency Is Associated with Reduced Local Inflammation in a Mouse Model of Experimental Colitis

Endocrinology ◽

10.1210/en.2007-1703 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3403-3409 ◽

Cited By ~ 28

Author(s):

Jérôme Gay ◽

Efi Kokkotou ◽

Michael O’Brien ◽

Charalabos Pothoulakis ◽

Katia P. Karalis

Keyword(s):

Mouse Model ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Experimental Colitis ◽

Neutrophil Infiltration ◽

Hormone Deficiency ◽

Trinitrobenzene Sulfonic Acid ◽

Inflammatory Bowel ◽

Proinflammatory Role ◽

Deficient Mice

CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. CRH is expressed in the intestine and up-regulated in patients with ulcerative colitis. However, its pathophysiological significance in intestinal inflammatory diseases has just started to emerge. In a mouse model of acute, trinitrobenzene sulfonic acid-induced experimental colitis, we demonstrate that, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism.

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Formyl Peptide Receptor 1-Mediated Glial Cell Activation in a Mouse Model of Cuprizone-Induced Demyelination

Journal of Molecular Neuroscience ◽

10.1007/s12031-017-0924-y ◽

2017 ◽

Vol 62 (2) ◽

pp. 232-243 ◽

Cited By ~ 4

Author(s):

Kai Bihler ◽

Eugenia Kress ◽

Stefan Esser ◽

Stella Nyamoya ◽

Simone C. Tauber ◽

...

Keyword(s):

Mouse Model ◽

Glial Cell ◽

Cell Activation ◽

Formyl Peptide Receptor ◽

Peptide Receptor ◽

Glial Cell Activation ◽

Formyl Peptide

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Mitochondrial N-formyl peptides cause airway contraction and lung neutrophil infiltration via formyl peptide receptor activation

Pulmonary Pharmacology & Therapeutics ◽

10.1016/j.pupt.2016.02.005 ◽

2016 ◽

Vol 37 ◽

pp. 49-56 ◽

Cited By ~ 24

Author(s):

Camilla Ferreira Wenceslau ◽

Theodora Szasz ◽

Cameron G. McCarthy ◽

Babak Baban ◽

Elizabeth NeSmith ◽

...

Keyword(s):

Neutrophil Infiltration ◽

Receptor Activation ◽

Formyl Peptide Receptor ◽

Peptide Receptor ◽

Formyl Peptide ◽

Formyl Peptides

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Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices

Journal of Neurophysiology ◽

10.1152/jn.00890.2015 ◽

2016 ◽

Vol 115 (3) ◽

pp. 1263-1272 ◽

Cited By ~ 21

Author(s):

Min-Yu Sun ◽

Yukitoshi Izumi ◽

Ann Benz ◽

Charles F. Zorumski ◽

Steven Mennerick

Keyword(s):

Brain Function ◽

Ex Vivo ◽

Hippocampal Slices ◽

Treatment Strategies ◽

Glucose Deprivation ◽

Wild Type ◽

Drug Candidates ◽

Excitatory Transmission ◽

The Central Nervous System ◽

New Treatment

N-methyl-d-aspartate receptors (NMDARs), a major subtype of glutamate receptors mediating excitatory transmission throughout the central nervous system (CNS), play critical roles in governing brain function and cognition. Because NMDAR dysfunction contributes to the etiology of neurological and psychiatric disorders including stroke and schizophrenia, NMDAR modulators are potential drug candidates. Our group recently demonstrated that the major brain cholesterol metabolite, 24 S-hydroxycholesterol (24S-HC), positively modulates NMDARs when exogenously administered. Here, we studied whether endogenous 24S-HC regulates NMDAR activity in hippocampal slices. In CYP46A1−/−(knockout; KO) slices where endogenous 24S-HC is greatly reduced, NMDAR tone, measured as NMDAR-to-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) excitatory postsynaptic current (EPSC) ratio, was reduced. This difference translated into more NMDAR-driven spiking in wild-type (WT) slices compared with KO slices. Application of SGE-301, a 24S-HC analog, had comparable potentiating effects on NMDAR EPSCs in both WT and KO slices, suggesting that endogenous 24S-HC does not saturate its NMDAR modulatory site in ex vivo slices. KO slices did not differ from WT slices in either spontaneous neurotransmission or in neuronal intrinsic excitability, and exhibited LTP indistinguishable from WT slices. However, KO slices exhibited higher resistance to persistent NMDAR-dependent depression of synaptic transmission induced by oxygen-glucose deprivation (OGD), an effect restored by SGE-301. Together, our results suggest that loss of positive NMDAR tone does not elicit compensatory changes in excitability or transmission, but it protects transmission against NMDAR-mediated dysfunction. We expect that manipulating this endogenous NMDAR modulator may offer new treatment strategies for neuropsychiatric dysfunction.

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