Fight Aging!

The immune system is a very complex, self-regulating system. In youth, it becomes inflamed in response to injury or pathogens, and that inflamed state is resolved once the immediate need is met. There are many pathways to rousing the immune system to inflammation, and some of these malfunction or are inappropriately stimulated in later life as a result of molecular damage, excess visceral fat tissue, senescent cell signaling, and so forth. This leads to chronic inflammation, overwhelming the equally diverse set mechanisms that are responsible for resolving inflammation after it has served its purpose.

Inflammation is important enough in aging and age-related disease to be a prominent target for therapies. Treatments to date have focused on bluntly sabotaging inflammatory signals that have been identified as important, which impairs necessary inflammation even as it reduces excessive inflammation to some degree. Since there are many such pathways to block, most of which are needed for the immune system to serve its purpose in defending the body, it may be that a better path forward is to strengthen the natural mechanisms responsible for resolving inflammation. Hence today's research materials, looking into how the immune system and nervous system interact via well-studied neurotransmitters. As this relationship is better understood, methods may emerge to intervene in order to more naturally reduce chronic inflammation.

Immune cells produce chemical messenger that prevents heart disease-related inflammation

The immune system's white blood cells, which are produced in the bone marrow, mostly help to defend against bacteria and injury, but sometimes they can turn against the body - for example, in cardiovascular disease, their inflammatory aggression can harm arteries and the heart. The nervous system plays a role in controlling blood cell production through chemical messengers or neurotransmitters. This is important in people exposed to stress, where stress hormones controlled by the sympathetic nervous system may increase bone marrow activity and cardiovascular inflammation in response to the neurotransmitter noradrenaline. The sympathetic nerves have a counter player - the parasympathetic nerves, which slow down responses and bring about a state of calm to the body, mainly through the neurotransmitter acetylcholine.

Because acetylcholine can have a protective effect against inflammation and heart disease, researchers studied this neurotransmitter in the bone marrow. "When we looked into how acetylcholine acts on the production of blood cells, we found that it does the expected - it reduces white blood cells, as opposed to noradrenaline, which increases them. What was unexpected though was the source of the neurotransmitter acetylcholine." The team found no evidence in the bone marrow of the typical nerve fibers that are known to release acetylcholine. Instead, B cells, which are themselves a type of white blood cell (most known for making antibodies), supplied the acetylcholine in the bone marrow. "Thus, B cells counter inflammation-even in the heart and the arteries - via dampening white blood cell production in the bone marrow. Surprisingly, they use a neurotransmitter to do so."

B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis

Autonomic nerves control organ function through the sympathetic and parasympathetic branches, which have opposite effects. In the bone marrow, sympathetic (adrenergic) nerves promote hematopoiesis; however, how parasympathetic (cholinergic) signals modulate hematopoiesis is unclear. Here, we show that B lymphocytes are an important source of acetylcholine, a neurotransmitter of the parasympathetic nervous system, which reduced hematopoiesis. Single-cell RNA sequencing identified nine clusters of cells that expressed the cholinergic α7 nicotinic receptor (Chrna7) in the bone marrow stem cell niche, including endothelial and mesenchymal stromal cells (MSCs). Deletion of B cell-derived acetylcholine resulted in the differential expression of various genes, including Cxcl12 in leptin receptor+ (LepR+) stromal cells. Pharmacologic inhibition of acetylcholine signaling increased the systemic supply of inflammatory myeloid cells in mice and humans with cardiovascular disease.