Microglia‐leucocyte axis in cerebral ischaemia and inflammation in the developing brain

Abstract

Development of the Central Nervous System (CNS) is reliant on the proper function of numerous intricately orchestrated mechanisms that mature independently, including constant communication between the CNS and the peripheral immune system. This review summarizes experimental knowledge of how cerebral ischaemia in infants and children alters physiological communication between leucocytes, brain immune cells, microglia and the neurovascular unit (NVU)—the “microglia‐leucocyte axis”—and contributes to acute and long‐term brain injury. We outline physiological development of CNS barriers in relation to microglial and leucocyte maturation and the plethora of mechanisms by which microglia and peripheral leucocytes communicate during postnatal period, including receptor‐mediated and intracellular inflammatory signalling, lipids, soluble factors and extracellular vesicles. We focus on the “microglia‐leucocyte axis” in rodent models of most common ischaemic brain diseases in the at‐term infants, hypoxic‐ischaemic encephalopathy (HIE) and focal arterial stroke and discuss commonalities and distinctions of immune‐neurovascular mechanisms in neonatal and childhood stroke compared to stroke in adults. Given that hypoxic and ischaemic brain damage involve Toll‐like receptor (TLR) activation, we discuss the modulatory role of viral and bacterial TLR2/3/4‐mediated infection in HIE, perinatal and childhood stroke. Furthermore, we provide perspective of the dynamics and contribution of the axis in cerebral ischaemia depending on the CNS maturational stage at the time of insult, and modulation independently and in consort by individual axis components and in a sex dependent ways. Improved understanding on how to modify crosstalk between microglia and leucocytes will aid in developing age‐appropriate therapies for infants and children who suffered cerebral ischaemia.

Transcriptome network analysis link perinatalStaphylococcus epidermidisinfection to microglia reprogramming in the immature hippocampus

“…In support, using LysM-eGFP mice, we found GFP positive myeloid cells in the hippocampus after infection. While leukocyte trafficking has been reported in several animal models of cerebral ischemia and inflammation in both neonatal and adult mice, contributing to acute and long-term brain injury, underlying mechanisms remain unclear (Rayasam et al, 2021). We previously showed monocyte and granulocyte infiltration to the brain 24 hours after cerebral hypoxia-ischemia (Smith et al, 2018).…”

“…Infiltration of leukocytes is an event often observed after blood-brain barrier (BBB) dysfunction, which is known to be associated with several neurological conditions (Rayasam et al, 2021). Therefore, we evaluated BBB permeability after S. epidermidis infection by measuring the plasma/brain ratio of glucose in the hippocampus of S. epidermidis-infected mice (Ek et al, 2015).…”

Persistent cortical and white matter inflammation after therapeutic hypothermia for ischemia in near-term fetal sheep

“…These differences in the time course of M1/M2 polarization between studies are likely related to differences in species and model; for example, that the rodent HI model leads to a severe stroke-like pattern of damage. Interestingly, there is growing evidence from rodent studies that inflammation and microglial responses to HI can be modulated in a sex-dependent manner [ 45 ]. However, the present study was not powered to assess sex differences.…”

Neutrophil modulation of behavior and cognition in health and disease: The unexplored role of an innate immune cell

“…69 Changes in brain physiology, such as after injury or disease, often leading to cognitive deficits have been correlated with increased neutrophil activation and recruitment. 33,[70][71][72][73][74][75][76] However, very few studies have shown a direct link between the activity of neutrophils and cognitive deficits. One such study showed that the recruitment and activity of neutrophils to the meninges following subarachnoid hemorrhage led to cognitive decline associated with the injury.…”

“…Changes in brain physiology, such as after injury or disease, often leading to cognitive deficits have been correlated with increased neutrophil activation and recruitment 33,70–76 . However, very few studies have shown a direct link between the activity of neutrophils and cognitive deficits.…”