title: Apolipoproteins and apolipoprotein mimetic peptides modulate phagocyte trafficking through chemotactic activity.
abstract: The plasma lipoprotein-associated apolipoproteins (apo) A-I and apoE have well described anti-inflammatory actions in the cardiovascular system, and mimetic peptides that retain these properties have been designed as therapeutics. The anti-inflammatory mechanisms of apolipoprotein mimetics, however, are incompletely defined. Whether circulating apolipoproteins and their mimetics regulate innate immune responses at mucosal surfaces, sites where transvascular emigration of leukocytes is required during inflammation, remains unclear. Herein, we report that Apoai(-/-) and Apoe(-/-) mice display enhanced recruitment of neutrophils to the airspace in response to both inhaled lipopolysaccharide and direct airway inoculation with CXCL1. Conversely, treatment with apoA-I (L-4F) or apoE (COG1410) mimetic peptides reduces airway neutrophilia. We identify suppression of CXCR2-directed chemotaxis as a mechanism underlying the apolipoprotein effect. Pursuing the possibility that L-4F might suppress chemotaxis through heterologous desensitization, we confirmed that L-4F itself induces chemotaxis of human PMNs and monocytes. L-4F, however, fails to induce a calcium flux. Further exploring structure-function relationships, we studied the alternate apoA-I mimetic L-37pA, a bihelical analog of L-4F with two Leu-Phe substitutions. We find that L-37pA induces calcium and chemotaxis through formyl peptide receptor (FPR)2/ALX, whereas its D-stereoisomer (i.e. D-37pA) blocks L-37pA signaling and induces chemotaxis but not calcium flux through an unidentified receptor. Taken together, apolipoprotein mimetic peptides are novel chemotactic agents that possess complex structure-activity relationships to multiple receptors, displaying anti-inflammatory efficacy against innate immune responses in the airway.
authors.affiliation: Laboratory of Respiratory Biology, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Madenspacher
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Azzam
authors.forename: Wanghua
authors.initials: W
authors.lastname: Gong
authors.forename: Kymberly M
authors.initials: KM
authors.lastname: Gowdy
authors.forename: Michael P
authors.initials: MP
authors.lastname: Vitek
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.forename: Ji Ming
authors.initials: JM
authors.lastname: Wang
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000494:pharmacology*; D040761:Biomimetic Materials / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects* / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects* / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C524548:COG1410; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C105101:FPR2 protein, human; C472885:L-4F peptide; D010455:Peptides; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C481578:formyl peptide receptor 2, mouse