Fig. 1: Proposed hypotheses for the divergent role of peripheral leucocytes in perinatal brain injury and influencing factors.

a Perinatal brain injury induced either by systemic infection and/or by hypoxic/ischaemic events triggers a variety of pathophysiological processes, i.e. endothelial (EC, red/orange), microglia (M, green) and astrocyte (A, brown/red) activation leading to neuronal (N) and oligodendrocyte (O) and progenitor cell (NPC/OPC: neuronal/oligodendrocyte progenitor cell) degeneration and impaired maturation of these precursor cells. Injury-induced activation of EC but also peripheral immune cell (purple) activation (stars) facilitate leucocyte infiltration into the injured brain (swung arrows) via concerted bidirectional molecular interactions involving selectins, integrins and chemokines. However, interactions between leucocytes and ECs also contribute to vascular inflammation and damage to the blood brain barrier composed of ECs connected by tight junction (TJ) proteins, normally tight packed basal membranes (BM) and astrocytic endfeet. Besides contributing to endothelial damage, peripheral leucocytes are supposed to act from the perivascular cuffs by the release of proteolytic enzymes accelerating access of peripheral immune cells to the injured CNS parenchyma, which is further supported by release of chemotactic molecules of activated astrocytes and microglia. Within the CNS, an intense interaction between infiltrated leucocytes and CNS-resident cells leads to the release of a variety of pro-inflammatory and neurotoxic molecules by all involved cell types (triangles). The exact cell source, the time course of expression for each cell type and the relevance for the evolution of brain injury warrants further investigation. So far, only few and very ubiquitous detrimental mechanisms have been proposed as effectors of peripheral immune cells, i.e. neutrophil extracellular trap (NET) formation, reactive oxygen species (ROS) production, increased activity of inflammatory and basal membrane degrading enzymes (e.g. COX-2 and MMPs), and release of pro-inflammatory cytokines. These detrimental effects were specifically ascribed to neutrophils, pro-inflammatory M1 monocytes/macrophages, natural killer (NK) cells and subsets of T cells (i.e. γδ T cells and CD4 Th17 cells). b Emerging evidence supports a divergent role of different leucocyte subsets not only promoting damage but also contributing to resolution of inflammation/injury and mediating protection and/or promoting repair. Proposed mechanisms include the release of anti-inflammatory cytokines and growth factors by, for example, regulatory T and B cells as well as protective myeloid cells (e.g. M2 polarized macrophages and CCR2⁺ monocytes). However, most of these hypotheses are based on data derived from adult brain injury models. The contribution of peripheral immune cells to protection and repair in a time-dependent manner following the initial insult is still unclear (question marks). Furthermore, it is important to note that peripheral immune cell subsets have not only been supposed to contribute to repair and regenerative processes but also to be essential for endogenous neurodevelopment, i.e., to support oligodendrogenesis and microglia development. Whether these mechanisms take place from the periphery or the perivascular areas (e.g. meninges and/or CP) and how these signals are mediated is still unclear (dashed arrows with question mark). c The general concept about neuroinflammatory/degenerative but possibly also reparative processes mediated by peripheral leucocytes is further challenged by well described sex differences in neurodevelopmental outcome and inflammatory processes. The often-reported increased risk and worse outcome for males is associated with increased innate immune responses in males, supported by the fact that only male mice are protected after depletion of peripheral myeloid cells. Whether such sex dichotomy also applies to cells of the adaptive immune system is still unclear. d Another major aspect to be considered according to the hypothesized processes in (a) is the maturational stage, since many of them (full arrows with question marks) are still derived from preclinical research in adult brain injury models. However, the immune system and the brain reveal different responses over the life span, reflected by a rather immunoregulatory response in the neonatal stage to limit excess inflammation and an increased capacity of CNS regeneration despite of increased vulnerability of the developing brain. Therefore, concepts cannot be translated unequivocally from the adult organism to the neonatal system. Further challenges, which need to be taken into account for the predicted mechanisms shown in (a), are different immune and brain developmental stages in preterm compared to term newborns.