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Modulating Macrophage Polarization through CCR2 Inhibition and Multivalent Engagement.
Deci, Michael B; Ferguson, Scott W; Scatigno, Sydney L; Nguyen, Juliane.
Afiliación
  • Deci MB; Department of Pharmaceutical Sciences, School of Pharmacy , University at Buffalo, The State University of New York , Buffalo , NY 14214 , United States.
  • Ferguson SW; Department of Pharmaceutical Sciences, School of Pharmacy , University at Buffalo, The State University of New York , Buffalo , NY 14214 , United States.
  • Scatigno SL; Department of Pharmaceutical Sciences, School of Pharmacy , University at Buffalo, The State University of New York , Buffalo , NY 14214 , United States.
  • Nguyen J; Department of Pharmaceutical Sciences, School of Pharmacy , University at Buffalo, The State University of New York , Buffalo , NY 14214 , United States.
Mol Pharm ; 15(7): 2721-2731, 2018 07 02.
Article en En | MEDLINE | ID: mdl-29791797
Excessive or prolonged recruitment of inflammatory monocytes to damaged tissue can significantly worsen patient outcomes. Monocytes migrate to sites of tissue inflammation in response to high local concentrations of CCL2, a chemokine that binds to and signals through the CCR2 receptor. While the role of CCR2 in cellular migration is well studied, it is unclear how CCR2 inhibition affects macrophage polarization and if multivalency can increase downstream signaling effects. Using affinity selection with a phage library, we identified a novel single-chain variable fragment (scFv) (58C) that binds specifically and with high affinity to the N-terminal domain of CCR2 ( KD = 59.8 nM). The newly identified 58C-scFv bound to native CCR2 expressed on macrophages and MDA-MB-231 cells, inhibited migration, and induced a pro-inflammatory M1-phenotype in macrophages. The M1/M2 macrophage phenotype ratio for monomeric 58C-scFv was significantly increased over the negative control by 1.0 × 104-fold (iNOS/Arg-1), 5.1 × 104-fold (iNOS/Mgl2), 3.4 × 105-fold (IL-6/Arg-1), and 1.7 × 106-fold (IL-6/Mgl2). The multivalent display of 58C-scFv on liposomes further reduced migration of both cell types by 25-40% and enhanced M1 polarization by 200% over monomeric 58C-scFv. These studies demonstrate that CCR2 inhibition polarizes macrophages toward an inflammatory M1 phenotype, and that multivalent engagement of CCR2 increases the effects of 58C-scFv on polarization and migration. These data provide important insights into the role of multivalency in modulating binding, downstream signaling, and cellular fate.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores CCR2 / Anticuerpos de Cadena Única / Activación de Macrófagos / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores CCR2 / Anticuerpos de Cadena Única / Activación de Macrófagos / Macrófagos Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Mol Pharm Asunto de la revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos