Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage

• Published in: Nature communications Vol. 8; no. 1; pp. 602 - 12
• Main Authors: Zhao, Xiurong, Ting, Shun-Ming, Liu, Chin-Hsuan, Sun, Guanghua, Kruzel, Marian, Roy-O’Reilly, Meaghan, Aronowski, Jaroslaw
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.09.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/127/1213; 631/250/2504/223/1699; 692/308/1426; 692/617/375/534; Animal models; Animals; Astrocytes; Bone marrow; Brain; Brain damage; Brain Edema; Brain injury; Cells, Cultured; Cerebral Cortex - cytology; Cerebral Hemorrhage - immunology; Cerebral Hemorrhage - metabolism; Cytokines; Cytotoxicity; Edema; Flow Cytometry; Head injuries; Hematoma; Hemorrhage; Humanities and Social Sciences; Immunomodulation; Immunoregulation; Inflammation; Injury prevention; Interleukin 27; Interleukin-27 - immunology; Interleukin-27 - pharmacology; Iron; Iron and steel making; Lactoferrin; Lactoferrin - metabolism; Lactoferrin - pharmacology; Leukocytes (neutrophilic); Mice; Microglia; Modulators; multidisciplinary; Neuromodulation; Neurons - drug effects; Neurons - metabolism; Neutrophil Infiltration - immunology; Neutrophils; Neutrophils - immunology; Oligodendroglia; Patient admissions; Rats; Reverse Transcriptase Polymerase Chain Reaction; Scavenging; Science; Science (multidisciplinary); STAT3 Transcription Factor - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-00770-7

Shortly after intracerebral hemorrhage, neutrophils infiltrate the intracerebral hemorrhage-injured brain. Once within the brain, neutrophils degranulate, releasing destructive molecules that may exacerbate brain damage. However, neutrophils also release beneficial molecules, including iron-scavenging lactoferrin that may limit hematoma/iron-mediated brain injury after intracerebral hemorrhage. Here, we show that the immunoregulatory cytokine interleukin-27 is upregulated centrally and peripherally after intracerebral hemorrhage. Data from rodent models indicate that interleukin-27 modifies neutrophil maturation in the bone marrow, suppressing their production of pro-inflammatory/cytotoxic products while increasing their production of beneficial iron-scavenging molecules, including lactoferrin. Finally, interleukin-27 or lactoferrin administration results in reduced edema, enhanced hematoma clearance, and improved neurological outcomes in an animal model of intracerebral hemorrhage. These results suggest that interleukin-27/lactoferrin-mediated modulations of neutrophil function may represent a therapeutically viable concept for the modification of neutrophils toward a “beneficial” phenotype for the treatment of intracerebral hemorrhage. Neutrophils are important modulators of tissue damage after intracerebral hemorrhage (ICH), but how this function is regulated is not clear. Here, the authors show interleukin-27 promotes the tissue-protecting functions of neutrophils via, at least partly, the induction of lactoferrin to present a potential therapy for ICH.