Peripheral myeloid cells contribute to brain injury in male neonatal mice

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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1344-9) contains supplementary material, which is available to authorized users.

Perinatal Opioid Exposure Primes the Peripheral Immune System Toward Hyperreactivity

“…Evidence from studies examining PBMCs isolated from adult humans suggests that sex differences in stimulated PBMC properties and secretion exist ( 105 – 107 ). While sex differences in secretion of PBMCs isolated at neonatal time points are not well-defined ( 35 , 37 ), evidence exists demonstrating sex-specific differences in brain inflammation following circulating myeloid cells depletion in neonatal mice ( 108 ) and that inflammatory responses following immune cell activation in the immature brain differ between males and females, as reviewed by Mallard et al ( 109 ). Thus, separate pooling of males and female peripheral blood from P7 pups for sex-specific analysis represents an important future direction.…”

Choroid plexus transcriptome and ultrastructure analysis reveals a TLR2-specific chemotaxis signature and cytoskeleton remodeling in leukocyte trafficking

“…Leukocyte migration to the CNS is a hallmark of many neurological diseases including neonatal encephalopathy (Smith et al, 2018). Leukocyte accumulation in CSF and subarachnoid spaces is also observed in some CNS pathologies, most markedly in meningitis (Wilson et al, 2010).…”

Preterm Brain Injury, Antenatal Triggers, and Therapeutics: Timing Is Key

“…Similarly, to microglia, macrophages are plastic in phenotype and can either exacerbate brain injury or promote regeneration. There is evidence that monocytes are recruited into the brain after HI as levels of monocyte chemoattractant protein-1 (MCP-1) increase acutely within the brain and in mouse models in which only mature myeloid cells from the periphery express an enhanced green fluorescent protein, fluorescence is detected 24 h and seven days after HI within the CNS [ 102 , 103 ]. In the same model, antibody-mediated depletion of monocytes was neuroprotective but only in male mice.…”

“…In the same model, antibody-mediated depletion of monocytes was neuroprotective but only in male mice. This suggests monocytes contribute to brain damage in male mice [ 102 ]. Contrarily, it has been shown that mice pre-conditioned with LPS generated splenic monocytes that protect the brain in a stroke model [ 104 ].…”