title: N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARγ agonist rosiglitazone.
abstract: OBJECTIVE
  Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor-γ dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor-γ activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome.
  
  
  METHODS
  Brain sections and cell suspensions were prepared from mice exposed to permanent distal middle cerebral artery occlusion. Double immunostaining with stereological counting of brain sections and flow-cytometry analysis of brain cell suspensions were performed.
  
  
  RESULTS
  Rosiglitazone accelerated neutrophil infiltration to the ischemic core, concomitantly to neuroprotection. Some neutrophils (≈31%) expressed M2 markers, namely Ym1 and CD206 (mannose receptor). After treatment with the peroxisome proliferator-activated receptor-γ agonist rosiglitazone, most neutrophils (≈77%) acquired an N2 phenotype. Interestingly, rosiglitazone increased neutrophil engulfment by microglia/macrophages, a clearance that preferentially affected the N2 subset.
  
  
  CONCLUSIONS
  We present the first evidence of neutrophil reprogramming toward an N2 phenotype in brain inflammation, which can be modulated by activation of the peroxisome proliferator-activated receptor-γ nuclear receptor. We also show that N2 polarization is associated with an increased neutrophil clearance, thus suggesting that this switch is a crucial event for resolution of inflammation that may participate in neuroprotection.
authors.affiliation: From the Unidad de Investigación Neurovascular, Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC) and Instituto de Investigación Sanitaria Hospital 12 de Octubre (i+12), Madrid, Spain (M.I.C., I.B., A.M., I.L., M.A.M.); Servicio de Neurología and Instituto de Investigación Sanitaria del Hospital Universitario de La Princesa, Madrid, Spain (F.N., J.V.); Arthritis and Inflammation Research Centre, University of Melbourne and Department of Medicine, Royal Melbourne Hospital, Melbourne, Australia (J.A.H.); and Centro de Investigaciones Biológicas, CSIC, Madrid, Spain (A.L.C.).
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Cuartero
authors.forename: Iván
authors.initials: I
authors.lastname: Ballesteros
authors.forename: Ana
authors.initials: A
authors.lastname: Moraga
authors.forename: Florentino
authors.initials: F
authors.lastname: Nombela
authors.forename: José
authors.initials: J
authors.lastname: Vivancos
authors.forename: John A
authors.initials: JA
authors.lastname: Hamilton
authors.forename: Ángel L
authors.initials: ÁL
authors.lastname: Corbí
authors.forename: Ignacio
authors.initials: I
authors.lastname: Lizasoain
authors.forename: María A
authors.initials: MA
authors.lastname: Moro
mesh_terms: D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists*; D000077154:Rosiglitazone; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone
keywords: immunomodulation; inflammation; phagocytosis