Abstract
BackgroundNeonatal brain injury is increasingly understood to be linked to inflammatory processes that involve specialised CNS and peripheral immune interactions. However, the role of peripheral myeloid cells in neonatal hypoxic-ischemic (HI) brain injury remains to be fully investigated.MethodsWe employed the Lys-EGFP-ki mouse that allows enhanced green fluorescent protein (EGFP)-positive mature myeloid cells of peripheral origin to be easily identified in the CNS. Using both flow cytometry and confocal microscopy, we investigated the accumulation of total EGFP+ myeloid cells and myeloid cell subtypes: inflammatory monocytes, resident monocytes and granulocytes, in the CNS for several weeks following induction of cerebral HI in postnatal day 9 mice. We used antibody treatment to curb brain infiltration of myeloid cells and subsequently evaluated HI-induced brain injury.ResultsWe demonstrate a temporally biphasic pattern of inflammatory monocyte and granulocyte infiltration, characterised by peak infiltration at 1 day and 7 days after hypoxia-ischemia. This occurs against a backdrop of continuous low-level resident monocyte infiltration. Antibody-mediated depletion of circulating myeloid cells reduced immune cell accumulation in the brain and reduced neuronal loss in male but not female mice.ConclusionThis study offers new insight into sex-dependent central-peripheral immune communication following neonatal brain injury and merits renewed interest in the roles of granulocytes and monocytes in lesion development.
Highlights
Neonatal brain injury is increasingly understood to be linked to inflammatory processes that involve specialised central nervous system (CNS) and peripheral immune interactions
Inflammatory monocytes represent a relatively short-lived population that is actively recruited to inflamed tissue [18, 19], whereas resident monocytes are physiologically recruited to non-inflamed tissue [18] and have the capacity to rapidly respond to tissue damage or infection [20]
We describe the differential dynamics of resident and inflammatory monocytes in this model and that inhibition of myeloid cell accumulation in the brain protects against HI injury in male, but not female, neonatal mice
Summary
Neonatal brain injury is increasingly understood to be linked to inflammatory processes that involve specialised CNS and peripheral immune interactions. Inflammatory monocytes represent a relatively short-lived population that is actively recruited to inflamed tissue [18, 19], whereas resident monocytes are physiologically recruited to non-inflamed tissue [18] and have the capacity to rapidly respond to tissue damage or infection [20]. These monocyte subsets display differential migratory dynamics in adult cerebral ischemia: inflammatory monocytes make a rapid but transient appearance, while resident monocytes display a delayed but progressive accumulation [21]. The inflammatory characteristics of each subset may underpin such dynamics: inflammatory monocytes upregulate inflammatory mediators including TNFα and IL1, while resident monocytes display a more reparative phenotype with elevated expression of genes involved in tissue remodelling such as arg and Fizz1 [20], drawing comparisons respective to M1 and M2 macrophage phenotypes [22]
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