title: Sex-specific regulation of chemokine Cxcl5/6 controls neutrophil recruitment and tissue injury in acute inflammatory states.
abstract: BACKGROUND
  Tissue infiltration by neutrophils during acute inflammatory states causes substantial tissue injury. While the magnitude of tissue neutrophil accumulation in innate immune responses is profoundly greater in males than females, fundamental aspects of the molecular mechanisms underlying these sex differences remain largely unknown.
  
  
  METHODS
  We investigated sex differences in neutrophil stimulation and recruitment in ischemia/reperfusion (I/R; mesenteric or renal) or carrageenan pleurisy in rats or mice, as well as skin injury in human volunteers. The induction of potent chemoattractive mediators (chemokines) and neutrophil adhesion molecules were measured by real-time PCR, flow cytometry, and protein assays.
  
  
  RESULTS
  Mesenteric I/R in age-matched Wistar rats resulted in substantially more neutrophil accumulation and tissue injury at 2 h reperfusion in males than females. Using intravital microscopy, we show that the immediate (<30 min) neutrophil response to I/R is similar in males and females but that prolonged neutrophil recruitment occurs in males at sites local and distal to inflammatory insult partly due to an increase in circulating neutrophil populations with elevated surface expression of adhesion molecules. Sex differences in neutrophil kinetics were correlated with sustained induction of chemokine Cxcl5 in the tissue, circulation, and bone marrow of males but not females. Furthermore, blockade of Cxcl5 in males prior to ischemia resulted in neutrophil responses that were similar in magnitude to those in females. Conversely, administration of Cxcl5 to males in the absence of I/R was sufficient to increase levels of systemic neutrophils. Cxcl5 treatment of bone marrow neutrophils in vitro caused substantial induction of neutrophil-mobilizing cytokine granulocyte colony-stimulating factor (GCSF) and expression of β2 integrin that accounts for sexual dimorphism in circulating neutrophil populations in I/R. Moreover, male Cxcl5-stimulated bone marrow neutrophils had an increased capacity to adhere to β2 integrin ligand ICAM-1, implicating a greater sensitivity of male leukocytes to Cxcl5-mediated activation. Differential induction of Cxcl5 (human CXCL6) between the sexes was also evident in murine renal I/R, rat pleurisy, and human skin blisters and correlated with the magnitude of neutrophil accumulation in tissues.
  
  
  CONCLUSIONS
  Our study reveals that sex-specific induction of chemokine Cxcl5/CXCL6 contributes to sexual dimorphism in neutrophil recruitment in diverse acute inflammatory responses partly due to increased stimulation and trafficking of bone marrow neutrophils in males.
authors.affiliation: Centre for Microvascular Research, London, EC1M 6BQ UK.
authors.forename: Shimona
authors.initials: S
authors.lastname: Madalli
authors.affiliation: Centre for Microvascular Research, London, EC1M 6BQ UK.
authors.forename: Martina
authors.initials: M
authors.lastname: Beyrau
authors.affiliation: Centre for Microvascular Research, London, EC1M 6BQ UK.
authors.forename: James
authors.initials: J
authors.lastname: Whiteford
authors.affiliation: Department of Cardiovascular Research, Max Delbrück Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
authors.forename: Johan
authors.initials: J
authors.lastname: Duchene
authors.affiliation: Centre for Microvascular Research, London, EC1M 6BQ UK.
authors.forename: Inderpal
authors.initials: I
authors.lastname: Singh Nandhra
authors.affiliation: Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, London, EC1M 6BQ UK.
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.affiliation: Department of Medicine, Rayne Institute, University College London, London, WC1 6JJ UK.
authors.forename: Madhur P
authors.initials: MP
authors.lastname: Motwani
authors.affiliation: Department of Medicine, Rayne Institute, University College London, London, WC1 6JJ UK.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Gilroy
authors.affiliation: Centre for Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and The London Medical School, Queen Mary University of London, London, EC1M 6BQ UK.
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.affiliation: Centre for Microvascular Research, London, EC1M 6BQ UK.
authors.forename: Sussan
authors.initials: S
authors.lastname: Nourshargh
authors.affiliation: Centre for Microvascular Research, London, EC1M 6BQ UK.
authors.forename: Ramona S
authors.initials: RS
authors.lastname: Scotland
keywords: Bone marrow; Gender; Ischemia/reperfusion; Leukocyte