Contemporary insights into neuroimmune interactions across development and aging

Abstract

Initially considered distinct systems with independent physiological functions, recent evidence highlights the crucial role of active crosstalk between the nervous and immune systems in regulating critical physiological and neurological processes and immunological homeostasis. The identification of a direct body-brain circuitry allowing the monitoring of peripheral inflammatory responses, a unique skull bone marrow source of immune cells to the central nervous system (CNS), and the physical interface of the blood-brain barrier with the meningeal system suggest direct intersystem interactions, which can be further modulated by the local tissue environment, allowing non-neurological factors to influence neurological outcomes and vice versa. While there is a recognized age-dependent decline in both neurological and immune system function, in part due to the natural accumulation of cellular defects and the development of chronic systemic inflammation, it is unclear if the pre-existing bidirectional feedback mechanisms between the neurological and peripheral immune system plays a role in shaping the system decline, beyond commonly investigated pathological conditions. In this review, we will explore the effect of aging on the bidirectional communication between the neurological and immunological systems and attempt to understand how the inevitable age-dependent alterations of the interaction may concurrently drive immunosenescence, normal neurological decline, and neuropathological progression.

Keywords: aging; immunosenescence; neurodegeneration; neuroimmune crosstalk; neurological decline.

Figure 1

Microglia dynamics during brain development. Primitive macrophage, the precursors of microglia, originate from the yolk sac and enters the developing brain at approximately E9.5 (top panel). These cells enter the developing brain primarily through the embryonic vasculature. The chemokine CXCL12, secreted by neural stem cells, guides the migration of primitive macrophages toward the interphase between the blood vasculature and the brain parenchyma. The lymphocyte function-associated antigen 1/Intercellular Adhesion Molecule-1 (LFA-1/ICAM-1) interaction is also proposed to facilitate trans-endothelial migration of these microglia precursors (middle panel). As the BBB matures between E14 and E19, tight junctions formed between endothelial cells, and astrocyte endfeet along with pericytes engage the vasculature, to reinforce barrier integrity. This results in a selective permeable interface that restricts the entry of peripheral immune cells into the CNS (bottom panel). Figure created with BioRender. Yeo, X. (2025) https://BioRender.com/uxni7uh.

Figure 2

Development of the PNS and immune system influence on its function. Embryonic development of the PNS, originating from neural crest cells that migrate and differentiate intro diverse neuronal and glial populations along peripheral nerve tracts (Top). Peripheral immune cells play a critical role in the regulation of PNS function and homeostasis. Although the contribution of immune cells to PNS development remains poorly understood, their involvement in peripheral nerve repair and regeneration following injury or under pathological systems is well-established (Bottom). Created with BioRender. Yeo, X. (2025) https://BioRender.com/uxni7uh.

Figure 3

Age-related changes in immune cells and the development of chronic inflammation in the CNS. Increased permeability of the BBB due to endothelial cell, pericyte, and astrocyte senescence and demise and an increase in the number of activated astrocytes and microglia leads to the recruitment of peripheral immune cells into the brain parenchyma. The altered immune cell (from periphery or resident to the brain) function and status with age results in the accumulation of senescent cells, cellular debris, and abnormally aggregated proteins, triggering further inflammatory responses within the brain. As such, the persistent inflammatory status and increasingly abundant cellular byproducts result in a positive feedback loop that damages and triggers death pathways in neurons (neurodegeneration). Created in BioRender. Yeo, X. (2025) https://BioRender.com/dwabb60.