Monocytes and Their Derivatives: Bridging Vascular and Neurodegenerative Pathology

Dear Colleagues,

Monocytes, a type of innate immune cell, are generated by hematopoietic stem cells in the bone marrow and subsequently enter the bloodstream. These cells are divided into three primary subsets based on their surface markers: classical, intermediate, and non-classical monocytes. In mice, these subsets are identified by markers such as CD11b, CD45, Ly6G, Ly6C, CX3CR1, and CCR2. Murine classical monocytes (Ly6C^high; CCR2⁺⁺; CX3CR1⁺), analogous to human classical monocytes (CD14⁺⁺CD16⁻), are primarily involved in inflammatory responses. Intermediate monocytes (Ly6C^int), similar to human intermediate monocytes (CD14⁺⁺CD16⁺), display moderate expression of these markers. Non-classical or patrolling monocytes (Ly6C^low; CCR2⁻; CX3CR1⁺⁺), corresponding to human non-classical monocytes (CD14⁺CD16⁺⁺), play roles in vascular surveillance and tissue repair. Upon migrating into tissues, monocytes differentiate into macrophages or dendritic cells, adapting to local microenvironments. In the brain, under pathological conditions, monocytes can differentiate into macrophages, contributing to the neuroinflammatory landscape observed in neurodegenerative diseases like Alzheimer’s disease (AD) and multiple sclerosis (MS). Conversely, following myocardial infarction (MI), monocytes infiltrate the heart and differentiate into diverse macrophage subsets. For instance, pro-inflammatory macrophages (Ly6C^high) are crucial in the early post-MI stages for clearing debris and initiating tissue repair, although they can also exacerbate inflammation if not properly regulated. Trem2^hi macrophages, identified in ischemic heart areas, resemble lipid-associated macrophages in metabolic diseases, indicating a conserved response mechanism across different conditions. Furthermore, recent studies have uncovered that monocyte infiltration into the brain post-MI can initiate neuropathological events leading to vascular dementia. Vascular dementia contributes to AD and other neurodegenerative conditions by reducing blood flow to the brain, leading to hypoxia and cellular damage. This disruption in vascular health can accelerate the formation of amyloid plaques and tau tangles in Alzheimer’s, exacerbate symptoms in mixed dementia, and worsen cognitive decline in conditions like Lewy body dementia and Parkinson’s disease dementia. This highlights the interconnectedness of vascular health and neurodegenerative diseases. In neurodegenerative diseases like AD, peripheral monocytes can infiltrate the brain, differentiate into macrophages, and participate in amyloid-β clearance. Modulating these cells, such as using NOD2 agonists to promote the conversion of inflammatory monocytes to patrolling monocytes, can enhance vascular amyloid-β clearance and delay disease progression. In MS, monocytes infiltrate the central nervous system (CNS) and contribute to both demyelination and tissue repair. Targeting monocytes and their differentiation pathways offers promising therapeutic avenues. For instance, CCR2 antagonists can modulate monocyte infiltration and function, potentially mitigating chronic inflammation and tissue damage in diseases like MS and cardiovascular conditions. Additionally, harnessing the plasticity of monocytes to skew their differentiation towards protective phenotypes could improve outcomes in neurodegenerative diseases.

In conclusion, monocytes are versatile immune cells with significant roles in both health and disease. Understanding their subsets, differentiation pathways, and functional contributions in various tissues, including the brain and heart, is crucial for developing targeted therapies for neurodegenerative and cardiovascular diseases. This Special Issue aims to gather studies focusing on monocytes, microglia, and macrophages within the context of neurodegenerative and cardiovascular diseases, which are pivotal in understanding and potentially intervening in the pathological processes of cerebral amyloid angiopathy (CAA) and other neurological conditions, including AD and MS. By exploring the roles and plasticity of these immune cells, we seek contributions that offer insights into their differentiation pathways, regulatory mechanisms, and therapeutic targeting, which could substantially influence the progression and treatment of these complex diseases. Contributions are invited from research that elucidates the functional dynamics of monocytes and their derivatives in the brain and heart, aiming to improve our understanding and management of the intertwined pathologies of vascular impairment and neurodegeneration.

Dr. Majid Ghareghani
Guest Editor

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