CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axes and their possible involvement in age-related macular degeneration

The causes of age-related macular degeneration (AMD) are not well understood. Due to demographic shifts in the industrialized world a growing number of people will develop AMD in the coming decades. To develop treatments it is essential to characterize the disease's pathogenic process. Over the past few years, numerous studies have focused on the role of chemotactic cytokines, also known as chemokines. Certain chemokines, such as CCL2 and CX3CL1, appear to be crucial in subretinal microglia and macrophage accumulation observed in AMD, and participate in the development of retinal degeneration as well as in choroidal neovascularization. This paper reviews the possible implications of CCL2 and CX3CL1 signaling in AMD. Expression patterns, single nucleotide polymorphisms (SNPs) association studies, chemokine and chemokine receptor knockout models are discussed. Future AMD treatments could target chemokines and/or their receptors

Rôles des chimiokines dans le développement de la dégénérescence maculaire liée à l’âge

International audienceRole of chemokines in the development of age-related macular degeneration. Age-related macular degeneration (AMD) is the main cause of irreversible blindness in industrialized nations. Recent research has emphasized the importance of inflam-matory processes in pathogenesis of this disease. Chemotactic cytokines also named chemokines are important mediators of inflammation and might have a role in development of this disease. They appear to be crucial in the subretinal microglia / macrophage accumulation observed in AMD and may participate in the development of retinal degeneration and in choroidal neovascularization. This paper reviews the possible implication of chemokines in the development of AMD.La dégénérescence maculaire liéeà l'âge (DMLA) est la principale cause de cécité irréversible dans les pays industrialisés. Lesétudes récentes mettent en exergue l'importance des processus inflammatoires dans le développement de la maladie. Les cytokines chimiotactiques, dénommées chimiokines, qui apparaissent comme des médiateurs importants de l'inflammation, pourraient jouer un rôle dans le développement de la DMLA. Plus particulièrement, elles semblent indispensables dans le processus d'accumulation des microglies/macrophages dans l'espace sous-rétinien observé au cours de la DMLA. Elles pourraient par conséquent partici-per au développement de la dégénérescence rétinienne et de la néovascularisation choroïdienne. Dans cette revue, nous décrirons l'implication des chimiokines et de leurs récepteurs dans le développement de la DMLA

Des peptides immunomodulateurs aux peptides opioïdes de la peau de rainettes latino-américaines (ou l'originalité d'un modèle)

La peau de grenouilles sécrète un grand nombre de peptides aux propriétés pharmacologiques remarquables. Ces peptides, produits en grande quantité, sont souvent similaires à ceux utilisés par les mammifères dans leur système nerveux central et endocrinien. Les peptides de grenouille représentent donc un modèle original pour l étude de peptides similaires chez l Homme. Nous avons mis en évidence la présence, dans la peau de Pachymedusa dacnicolor et Phyllomedusa sauvagei, de peptides ayant des propriétés immunomodulatrices sur les cellules immunitaires humaines ainsi que l importance de la structure de type beta-amyloïdogénique pour l activité biologique de l un de ces peptides, la dermaseptine S9. Nous avons enfin localisé dans les granules des glandes séreuses de la peau de Phyllomedusa bicolor, un peptide antimicrobien, la dermaseptine B2, et un peptide opioïde, la deltorphine I, très similaire aux opioïdes de mammifères mais contenant un acide aminé D dans sa séquence.PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Post-translational amino acid racemization in the frog skin peptide deltorphin I in the secretion granules of cutaneous serous glands.

International audienceThe dermal glands of the South American hylid frog Phyllomedusa bicolor synthesize and expel huge amounts of cationic, alpha-helical, 24- to 33-residue antimicrobial peptides, the dermaseptins B. These glands also produce a wide array of peptides that are similar to mammalian hormones and neuropeptides, including a heptapeptide opioid containing a D-amino acid, deltorphin I (Tyr-DAla-Phe-Asp-Val-Val-Gly NH2). Its biological activity is due to the racemization of L-Ala2 to D-Ala. The dermaseptins B and deltorphins are all derived from a single family of precursor polypeptides that have an N-terminal preprosequence that is remarkably well conserved, although the progenitor sequences giving rise to mature opioid or antimicrobial peptides are markedly different. Monoclonal and polyclonal antibodies were used to examine the cellular and ultrastructural distributions of deltorphin I and dermaseptin B in the serous glands by immunofluoresence confocal microscopy and immunogold-electron microscopy. Preprodeltorphin I and preprodermaseptins B are sorted into the regulated pathway of secretion, where they are processed to give the mature products. Deltorphin I, [l-Ala2]-deltorphin I and dermaseptin B are all stored together in secretion granules which accumulate in the cytoplasm of all serous glands. We conclude that the L- to D-amino acid isomerization of the deltorphin I occurs in the secretory granules as a post-translational event. Thus the specificity of isomerization depends on the presence of structural and/or conformational determinants in the peptide N-terminus surrounding the isomerization site

Rôles des chimiokines dans le développement de la dégénérescence maculaire liée à l’âge

La dégénérescence maculaire liée à l’âge (DMLA) est la principale cause de cécité irréversible dans les pays industrialisés. Les études récentes mettent en exergue l’importance des processus inflammatoires dans le développement de la maladie. Les cytokines chimiotactiques, dénommées chimiokines, qui apparaissent comme des médiateurs importants de l’inflammation, pourraient jouer un rôle dans le développement de la DMLA. Plus particulièrement, elles semblent indispensables dans le processus d’accumulation des microglies/macrophages dans l’espace sous-rétinien observé au cours de la DMLA. Elles pourraient par conséquent participer au développement de la dégénérescence rétinienne et de la néovascularisation choroïdienne. Dans cette revue, nous décrirons l’implication des chimiokines et de leurs récepteurs dans le développement de la DMLA

Pachymodulin, a new functional formyl peptide receptor 2 (FPR2) peptidic ligand isolated from frog skin, has Janus-like immunomodulatory capacities.

International audienceRecruitment of leukocytes is essential in order to fight infections or to heal injuries; however excessive and/or prolonged responses favor the development of major inflammatory pathologies, such as cardiovascular or neurodegenerative diseases. Thus, it is of great interest to seek for novel compounds that can regulate leukocytes recruitment depending on the degree of inflammation. We have isolated and characterized by different chromatographic techniques, mass spectrometry and Edman sequencing a new hexapeptide (SSLSKL) from the Mexican frog Pachymedusa dacnicolor, which we named Pachymodulin. In vitro, pachymodulin promotes the migration of leukocytes through the binding and activation of the human and mouse N-formyl peptide receptor 2 (huFPR2). In vivo, it exhibits opposite biological activities: under homeostatic conditions, pachymodulin induces the recruitment of leukocytes, whereas under inflammatory conditions, it inhibits this process. Therefore, Pachymodulin represents an interesting template in the quest to design new immunomodulatory drugs in the therapy of immune-related diseases

Dermaseptin DA4, although closely related to dermaseptin B2, presents chemotactic and Gram-negative selective bactericidal activities.

International audienceAntimicrobial peptides participate in innate host defense by directly eliminating pathogens as a result of their ability to damage the microbial membrane and by providing danger signals that will recruit innate immune cells to the site of infection. Dermaseptin DA4 (DRS-DA4), a new antimicrobial peptide of the dermaseptin superfamily, was identified based on its chemotactic properties, contrasting with the currently used microbicidal properties assessment. The peptide was isolated and purified by size exclusion HPLC and RP-HPLC from the skin of the Mexican frog, Pachymedusa dacnicolor. MS and amino acid sequence analyses were consistent with the structure GMWSKIKNAGKAAKAAAKAAGKAALGAVSEAM. CD experiments showed that, unlike most antimicrobial peptides of the dermaseptin superfamily, DRS-DA4 is not structured in the presence of zwitterionic lipids. DRS-DA4 is a potent chemoattractant for human leukocytes and is devoid of hemolytic activity; in addition, bactericidal tests and membrane perturbation assays on model membranes and on Escherichia coli and Staphylococcus aureus strains have shown that the antibacterial effects of DRS-DA4 and permeabilization of the inner membrane are exclusively selective for Gram-negative bacteria. Interestingly, despite high sequence homology with dermaseptin S4, dermaseptin B2 was not able to induce directional migration of leukocytes, and displayed a broader bactericidal spectrum. A detailed structure-function analysis of closely related peptides with different capabilities, such as DRS-DA4 and dermaseptin B2, is critical for the design of new molecules with specific attributes to modulate immunity and/or act as microbicidal agents

Pachymodulin, a New Functional Formyl Peptide Receptor 2 Peptidic Ligand Isolated from Frog Skin Has Janus-like Immunomodulatory Capacities

Recruitment of leukocytes is essential to fight infections or to heal injuries; however, excessive and/or prolonged responses favor the development of major inflammatory pathologies, such as cardiovascular or neurodegenerative diseases. Thus, it is of great interest to seek novel compounds that can regulate leukocyte recruitment depending on the degree of inflammation. We have isolated and characterized, by different chromatographic techniques, mass spectrometry, and Edman sequencing, a new hexapeptide (SSLSKL) from the Mexican frog <i>Pachymedusa dacnicolor,</i> which we named pachymodulin. In vitro, pachymodulin promotes the migration of leukocytes through the binding and activation of the human and mouse <i>N</i>-formyl peptide receptor 2 (huFPR2). In vivo, it exhibits opposite biological activities: under homeostatic conditions, pachymodulin induces the recruitment of leukocytes, whereas under inflammatory conditions, it inhibits this process. Therefore, pachymodulin represents an interesting template in the quest to design new immunomodulatory drugs in the therapy of immune-related diseases

Comparative study of two plasticins: specificity, interfacial behavior, and bactericidal activity.

International audienceA comparative study was designed to evaluate the staphylococcidal efficiency of two sequence-related plasticins from the dermaseptin superfamily we screened previously. Their bactericidal activities against Staphylococcus aureus as well as their chemotactic potential were investigated. The impact of the GraS/GraR two-component system involved in regulating resistance to cationic antimicrobial peptides (CAMPs) was evaluated. Membrane disturbing activity was quantified by membrane depolarization assays using the diS-C3 probe and by membrane integrity assays measuring beta-galactosidase activity with recombinant strain ST1065 reflecting compromised membranes and cytoplasmic leakage. Interactions of plasticins with membrane models composed of either zwitterionic lipids mimicking the S. aureus membrane of CAMP-resistant strains or anionic lipids mimicking the negative charge-depleted membrane of CAMP-sensitive strains were analyzed by jointed Brewster angle microscopy (BAM), polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS), and differential scanning calorimetry (DSC) to yield detailed information about the macroscopic interfacial organization, in situ conformation, orientation of the peptides at the lipid-solvent interface, and lipid-phase disturbance. We clearly found evidence of distinct interfacial behaviors of plasticins we linked to the distribution of charges along the peptides and structural interconversion properties at the membrane interface. Our results also suggest that amidation might play a key role in GraS/GraR-mediated CAMP sensing at the bacterial surface