Journal Article

Monocytes in neonatal stroke and hypoxic‐ischemic encephalopathy: Pathophysiological mechanisms and therapeutic possibilities

Pimentel‐Coelho, Pedro M.

2023

Overview

Neonatal arterial ischemic stroke (NAIS) and neonatal hypoxic‐ischemic encephalopathy (HIE) are common causes of neurological impairments in infants, for which treatment options are very limited. NAIS and HIE induce an innate immune response that involves the recruitment of peripheral immune cells, including monocytes, into the brain. Monocytes and monocyte‐derived cells have the potential to contribute to both harmful and beneficial pathophysiological processes, such as neuroinflammation and brain repair, but their roles in NAIS and HIE remain poorly understood. Furthermore, recent evidence indicates that monocyte‐derived macrophages can persist in the brain for several months following NAIS and HIE in mice, with possible long‐lasting consequences that are still unknown. This review provides a comprehensive overview of the mechanisms of monocyte infiltration and their potential functions in the ischemic brain, focusing on HIE and NAIS. Therapeutic strategies targeting monocytes and the possibility of using monocytes for cell‐based therapies are also discussed. Monocytes and monocyte‐derived cells in hypoxic‐ischemic encephalopathy (HIE) and neonatal arterial ischemic stroke (NAIS). (A) The origin of monocytes infiltrating the brain in neonatal HIE and NAIS has yet to be investigated, including the possibility that they originate from various sources, such as the spleen and bone marrow. (B) Monocytes can infiltrate the brain through different routes, but it is not yet known whether they can migrate from the meninges to the brain parenchyma after HIE and NAIS. (C) Monocytes infiltrate the brain in the first hours and days following HIE and NAIS, and chronic monocyte infiltration has been observed in HIE models. Monocytes can differentiate into macrophages and microglia‐like cells, which can persist in the brain during the chronic phase of NAIS and HIE. Key points Monocytes are recruited to the brain within the first days following neonatal arterial ischemic stroke (NAIS) and hypoxic‐ischemic encephalopathy (HIE). More severe lesions or a combination of HIE and systemic inflammatory insults lead to more robust recruitment of monocytes to the brain. Monocytes differentiate into macrophages and microglia‐like cells, which can remain in the brain for several months following NAIS and HIE. CCR2 signaling is critical for monocyte infiltration and represents a potential therapeutic target. The outcomes of CCR2 inhibition or knockout vary depending on the HIE model used, highlighting the need for more studies in different models. Models of cerebral ischemia in neonates and adults indicate that monocytes may contribute to both brain damage, through their pro‐inflammatory activity and ability to modify perineuronal nets, and brain repair and functional recovery, through efferocytosis and their role in vascular repair. Umbilical cord blood monocytes and preconditioned monocytes could be used for the development of cell‐based therapies. Pharmacological interventions targeting monocyte infiltration or function require further testing in experimental models of HIE and NAIS.

• Publisher: John Wiley & Sons, Inc,Carlos Chagas Filho Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil,Wiley
• Subject: Alzheimer's disease / Antigens / bone marrow / Brain damage / Carotid arteries / cerebral ischemia / Dendritic cells / Genes / Hypoxia / Insulin-like growth factors / Ischemia / microglia / monocytes / monocyte‐derived macrophages / Morphology / neonatal brain injury / neonatal hypoxia‐ischemia / perinatal stroke / Veins & arteries