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

Abstract

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.

Immune changes in peripheral blood and hematoma of patients with intracerebral hemorrhage

“…Shortly after ICH, neutrophils infiltrate into the hemorrhagic brain and contribute to the secondary brain injury by releasing pro‐inflammatory factors, reactive oxygen species, proteases, and matrix metalloproteinases . Recently, neutrophils were reported to have a beneficial effect in a rodent blood‐induced ICH model . In the ischemic brain, infiltrating neutrophils show a pro‐inflammatory N1 phenotype or an anti‐inflammatory N2 phenotype .…”

“…19 In the ischemic brain, infiltrating neutrophils show a pro-inflammatory N1 phenotype or an anti-inflammatory N2 phenotype. 46,58 Although previous studies have revealed that neutrophils infiltrate the hemorrhagic brain of animal models and undergo polarization, 19,64 to our knowledge there are no reports of neutrophil phenotype in ICH patients. CD45 + CD11b + Ly6G high and CD45 + CD11b + Ly6G low have been used to stratify the population of neutrophils in animals.…”

“…14,15 The reasons for the bidirectional role of immunocytes and inflammatory cytokines in the hemorrhagic brain and peripheral organs may relate to the different characteristics of their components and to the opposing effects of the different phenotypes of microglia/macrophages (M/MΦ) and neutrophils. 5,13,[16][17][18][19] In animal studies, accumulation of microglia and infiltration of macrophages, lymphocytes, and dendritic cells (DCs) have been observed in hemorrhagic brain. [4][5][6]20 M/ MΦ with both M1-and M2-like phenotypes have also been detected in the peripheral blood and perihematoma tissue of animals with ICH.…”

Neutrophils as effectors of vascular inflammation

“…This population displays neuroprotective features, limits inflammation and promotes resolution . Alternative neutrophil subsets with iron‐scavenging and neuroprotective properties during intracerebral haemorrhage have also been reported . Thus, neutrophils perform dual roles in the progression of ischaemic brain injury: during the early stages, they drive inflammation, and at later stages, they promote resolution.…”

“…88 Alternative neutrophil subsets with iron-scavenging and neuroprotective properties during intracerebral haemorrhage have also been reported. 89 Thus, neutrophils perform dual roles in the progression of ischaemic brain injury: during the early stages, they drive inflammation, and at later stages, they promote resolution. This duality suggests that targeting bulk neutrophil infiltration into the ischaemic core may not be an optimal strategy towards the treatment of stroke.…”