Nature: Major progress!

Click the blue word to follow us Atherosclerotic plaques form when lipoproteins and immune cells build up on the inner surface of arteries
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Immune cells in these plaques initiate an inflammatory signaling cascade that causes leukocytes to infiltrate the adventitia of the arteries
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When these leukocytes further accumulate near the plaque, they form adventitial tertiary lymphoid organs that further enhance the inflammatory response
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Atherosclerotic plaques wreak havoc on the cardiovascular system, narrowing blood vessels, reducing blood and oxygen delivery to vital organs, and causing heart attacks and strokes
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Inflammation triggered by immune cells is thought to be a major factor in plaque formation
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 The adventitia is an important part of the blood vessel wall and is the most closely related part of the nervous system and angiogenesis
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Studies have demonstrated the existence of neuroimmune-vascular junctions in the adventitial segments of atherosclerotic disease in mice and humans, as shown by the formation of growth cones near the axon terminals of immune cells and smooth muscle cells
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On April 27, 2022, the joint research team of Andreas JR Habenicht of the University of Munich in Germany revealed that the neuroimmune-vascular interface regulates the formation of atherosclerotic plaques through the brain-brain circuit
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Apolipoprotein E knockout mice are a common model for studying atherosclerosis, and the researchers used high-resolution imaging to find increased axonal density in segments adjacent to atherosclerotic plaques
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The density of axons in the adventitial tertiary lymphoid organ is approximately 40 times higher than that in normal mice
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Figure 1; Schematic representation of 3D reconstruction of the neuroimmune-vascular junction.
The tissue clearing technique further revealed that the axons of the celiac ganglion (CG) and sympathetic ganglia extend into the adventitia of the aorta and form the neuroimmune-vascular junction interface
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This structural connection also occurs in tissue from patients with atherosclerosis
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Figure 2: Single-cell sequencing of arterial tissue Single-cell sequencing found that the expression of genes involved in axonogenesis, axon guidance and synaptic transmission was up-regulated in arterial vascular tissue of apolipoprotein E knockout mice, further confirming the existence of axonogenesis in arterial vascular tissue
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In addition, apolipoprotein E knockout mice expressed tyrosine hydroxylase, calcitonin gene-related peptide, and transient receptor potential vanilloid receptor 1 in axons surrounding atherosclerotic plaques
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This suggests that sympathetic and nociceptive axon terminals directly innervate the adventitia
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By injecting retrograde tracer virus, researchers found that adventitial tertiary lymphoid organs receive not only peripheral nervous system perivascular ganglion, celiac ganglion (CG), and sympathetic ganglia input, but also intermediolateral neurons in the spinal cord , raphe pallor nucleus, paraventricular nucleus of the hypothalamus and other central nervous system inputs
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Neurons in the dorsal and ventral horn regions of the spinal cord, the raphe pallor nucleus, the paraventricular nucleus of the hypothalamus, the parabrachial nucleus, and the central nucleus of the amygdala were significantly activated in apolipoprotein E knockout mice
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These anatomical structures suggest that adventitial tertiary lymphoid organs are connected to the central nervous system via ganglionic structures of the peripheral nervous system, forming cerebral-arterial circuits
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The brain-arterial circuit is activated in aged mice
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Both 6-hydroxydopamine chemical disruption of sympathetic nerve fibers or celiac ganglionectomy can reduce sympathetic nerve fiber density and levels of the sympathetic neurotransmitter norepinephrine, progressively smaller adventitial tertiary lymphoid organs, and a Immune T- and B-cell infiltration was reduced, tertiary lymphoid organs disappeared after a few days, and the volume of sclerotic plaques was reduced
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Neuroimmune interactions are present in tumors, obesity, thermoregulation, central nervous system disease, and inflammatory bowel disease
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This paper reveals that a similar interaction exists in vascular disease: the neuroimmune-vascular interface acts as a sensor and effector in the arterial-brain circuit, driving atherosclerotic plaque formation
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[References] 1.
https://doi.
org/10.
1038/s41586-022-04673-6 The pictures in the text are from references