Summary & Contents
- The cell danger response (CDR) is a cellular-initiated threat involving the signaling of extracellular nucleotides such as ATP and ADP
- Extracellular ATP is a potent purinergic signaling molecule involved in inflammation
- Mast cell activation disorder (MCAS or MCAD) involves the degranulation of mast cells and release of numerous chemical messengers and inflammatory processes
- Extracellular ATP triggers mast cells to degranulate
- Natural therapeutic agents such as quercitin, salvia and baicalin may act to inhibit extracellular ATP binding and purinergic signaling
The cell danger response (CDR) is a cellular-initiated response to threat, such as infections and toxins. The CDR research has been pioneered by Robert Naviaux, MD, PhD (12). Much of the earlier work exploring cell danger signaling has been elucidated by the identification of DAMPs (damage associated molecular patterns) and PAMP’s (pathogen associated molecular patterns). Essentially all of these are similar mechanisms that involve various cell-initiated responses to cell danger.
A central part of the CDR involves cells throwing off purine nucleotides ATP and ADP into the extracellular space. This event results in a significant change in how cells function and behave, including a downshift in metabolic activities such as altered redox and nutrient availability, reduction in oxygen consumption by the mitochondria and a rise in cytosolic oxygen and ROS’s (reactive oxygen species). The extracellular ATP becomes a key signaling molecule that alerts neighboring cells to the threat, as well as functions to recruit immune cells and cytokines to sustain the CDR. Under normal conditions, a cell danger response will recede once the threat has been effectively resolved. It has been observed however, that individuals with certain conditions (such as autism) cannot resolve the CDR, and normal cell biology is significantly compromised. The trial studies by Naviaux et al found that the administration of the drug Suramin given at small doses intravenously, normalizes the cell danger signaling and markedly improves the presenting symptoms in autism (11). Suramin works by blocking extracellular ATP.
Extracellular ATP & Mast Cell Activation Disorders
ATP is the form of chemical energy cells use to function. However, ATP also can become an important signaling molecule when it concentrates in the extracellular environment. The actions of extracellular ATP (and other purine-containing nucleotides) is mediated by “purinergic signaling”.
Features of Extracellular ATP and Purinergic Signaling include:
- The pain response within the CNS (central nervous system) and peripheral tissues (1)
- Migration of stem cells (3)
- Learning, behavior, memory and synaptic plasticity (2)
- Blood platelet aggregation (4)
- Immune cell activation (macrophages and mast cells) (4)
- Proliferation and differentiation of keratinocytes (13)
- Promotion of extracellular matrix formation of intervertebral disc cells (14)
Mast cell activation syndromes (MCAD or MCAS) are an increasingly problematic concern and common clinical feature, especially among those with chronic illness. Mast cells are immune cells that play a dual function of repairing tissues and increasing new blood vessels as well as promoting inflammatory and allergic reactions. Mast cells express IgE (immunoglobulin E) which can trigger an allergic response as well as anaphylaxis.
Symptoms of Mast Cell Activation Disorders (MCAS or MCAD):
- Itching of the skin or pruritus
- Red bumps on the surface of the skin that itch
- Swelling of the eyes or throat following exposure to a suspected allergen
- Wheezing or difficulty breathing following exposure to an allergen or antigen
- Heart palpitations following a food like peanuts, dairy, wheat, corn, soy or other
- Swelling of the skin
- Brain fog or disorientation following exposure to an allergen or antigen
Mast cell activation and degranulation involves the release of several mediators such as histamine, serotonin, eicosanoids such as thromboxanes, leukotrienes and prostaglandins, as well as inflammatory cytokines like TNF-alpha, chemokines and IL-4. Additionally, mast cells will store and release ATP into the extracellular environment (5). The result is an inflammatory response that can have various systemic and localized effects.
What is significant is that the process by which mast cells are activated is through DAMPs (damage associated molecular patterns) and PAMP’s (pathogen associated molecular patterns). Extracellular ATP binds to the purinergic receptors on the surface of mast cells triggering mast cells to degranulate (6), and this process also mediates how mast cells cause intestinal inflammation (7). Complicating matters is that mast cells also release ATP into the extracellular milieu, thereby perpetuating the ATP-activated purinergic signaling and danger responses.
It stands to reason that resolving the immunological threat that is triggering mast cell activation should be the first order of business. This usually includes repeat offenders such as: toxins, mold and foods allergies. The second order of business includes finding new ways of stabilizing mast cells, especially the use of purinergic receptor mediators and antagonists.
Purinergic receptors don’t only exist on the surfaces of mast cells. They also exist in many different tissues and cell types in the body, including neural tissues, glial cells, astrocytes, as well as regions of the brain and spinal cord (8). The binding of extracellular ATP to many types of purinergic receptors can incite potent inflammatory mechanisms in the brain and neural tissues, such as NF-κ beta and T-cell activation from microglial cells (20, 21).
Activation of purinergic signaling in various tissues is associated with numerous diseases, such as ALS, Alzheimer’s, Huntington’s Disease, cancer, ischemia, autoimmune diseases as well as Lyme disease (9) and neuropathic pain disorders (8, 10).
Purinergic Signaling Antagonists: Possible Treatments
Aside from drugs like Suramin which block extracellular ATP, its worth investigating possible natural product agents, botanicals and nutraceuticals which may inhibit or antagonize extracellular ATP. This may lead to new ways of treating complex illnesses, including complications such as mast cell disorders. Of interest is that purinergic receptor antagonists are often anti-platelet compounds. To date there is not a considerable amount of research involving purinergic signaling for botanicals.
- Salvia miltiorrhiza, a Chinese herbal medicine contains Salvianolic acids, which are anti-platelet agents that block the purinergic receptor P2Y12 (15). Tanshinones, which are also salvia constituents have been shown in vitro to inhibit mast cell degranulation (17). Dantonic, a salvia-based, trademarked botanical compound undergoing clinical trials has reportedly inhibited mast cell degranulation (18).
- Baicalin, a derivative from the Chinese herb Scutilleria baicalensis inhibits the P2X3 purinergic receptor, and was found to mediate myocardial ischemic injury and accumulation of extracellular ATP (16).
- Quercetin is a well known mast cell stabilizer. Though currently unconfirmed, Quercetin is a probable candidate for inhibiting the binding of extracellular purines. Quercetin acts by inhibiting the uptake of calcium in mast cells. ATP binding of purinergic receptors enables calcium influx, which leads to a process of degranulation.
- Kaempferol, a bioflavonoid found in foods like cruciferous vegetables was studied as a purinergic receptor antagonist in HIV-1 target cells. Kaempferol inhibited or antagonized P2Y2 purinergic receptors on target cells, leading to reduced HIV-1-induced cell death and infection (22).
- On the other hand a study on ginseng found that its constituents were potent agonists of the P2Y7 receptor (19). Herbalists often recommend against “Qi tonics” such as ginseng during acute illness. Perhaps this is corroborating evidence as to why.