Neurotensin – crh – mast cell – stress exacerbations
A study published in PLoS One indicates the presence of distinctive interactions between neurotensin (NT), corticotropin-releasing hormone (CRH) and mast cells that may be involved in inflammatory- and/or stress-related diseases.
Psychological stress is known to aggravate asthma, migraines and certain autoimmune/inflammatory diseases. Although the mechanisms of stress-induced exacerbations of these conditions are not fully understood, several studies indicate that mast cells may play an important role in this process.
Mast cells are found in many body’s tissues, typically associated with blood vessels. In several organs, including the lymphoid tissue, a close spatial relationship between peptidergic nerve fibers and mast cells, T cells and macrophages is often observed.
The close juxtaposition of mast cells clusters to nerve fibers may contribute to their stimulation by neuropeptides and neurotransmitters as well as by acute psychological stress.
Neuropeptides such as peripheral CRH and substance P (SP) are potent mast cell secretagogues. Thus, acute stress might induce pro-inflammatory activities in certain tissues through neural activation of the peripheral CRH/SP–mast cell–histamine axis.
Recently, neurotensin (NT), a vasoactive 13-amino acid peptide, identified and isolated in the 1970s (for short overview and its actions, see our previous news report), has been implicated in this process. Previous research indicates that neurotensin is involved in the skin mast cell degranulation induced by immobilization stress. The neuropeptide also increases vascular permeability through mast cell activation. Mast cells express neurotensin receptors (NTRs) and their stimulation results in histamine release, whereas intravenous injection of neurotensin increases the level of blood histamine.
In the PLoS One study, Konstantinos–Dionysios Alysandratos and colleagues from the Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, Massachusetts, demonstrate that neurotensin triggers human mast cell degranulation, stimulates human mast cells to release vascular endothelial growth factor (VEGF) and augments the effect of CRH on VEGF release through a NTR specific manner.
The study also indicates the involvement of NF-kB activation in this process, and that neurotensin induces CRHR-1 expression and CRH can induce NTR expression on mast cells. Previous studies have also indicated that NTR activation leads to release of IL-8 and TNF, which can further promote inflammation.
The authors suggest that the interactions between neurotensin and CRH, resulting in mast cells activation and degranulation might influence the onset and/or course of autoimmune/inflammatory or allergic diseases.
SOURCE: PLoS One, 2012;7(11): e48934. doi: 10.1371/journal.pone.0048934. Epub 2012 Nov 14
Updates
A 2016 study by Irene Tsilioni et al. demonstrates that the neuropeptides corticotropin-releasing hormone (CRH), substance P (SP), and SP-structurally-related hemokinin-1 (HK-1) are significantly elevated in the serum of Fibromyalgia syndrome (FMS) patients in comparison with controls. This is the first time to our knowledge that CRH and HK-1 are shown to be increased in the serum of FMS patients.
These findings of significantly elevated serum levels of the neuropeptides CRH, SP, and SP-structurally-related hemokinin-1 (HK-1), as well as the cytokines IL-6 and TNF, in FMS patients compared with healthy controls may prove to be diagnostically useful.
A 2020 review by Theoharis C Theoharides searched PubMed between 1950 and 2019 using the following terms: allergies, anaphylaxis, atopic diseases, corticotropin-releasing hormone, inflammation, hypothalamic-pituitary-adrenal (HPA) axis, mast cells, mastocytosis, neuropeptides, psychological stress, neurotensin (NT), and substance P (SP).
The major conclusion: psychological stress worsens many diseases, especially asthma, atopic dermatitis, and mastocytosis. This effect is mediated through mast cells (MCs) stimulated by neuropeptides, especially corticotropin-releasing hormone, neurotensin, and substance P, a process augmented by interleukin-33.
Importantly, psychological stress augments allergic activation of MCs, but the available human evidence indicates that stress also stimulates MCs through CRH directly or together with other peptides to release proinflammatory molecules that contribute to the pathogenesis of atopic diseases. Thus, understanding how stress stimulates MCs is important in advancing treatments for diseases that worsen with stress.
A 2023 review by Dorina Lauritano et al. explores the current understanding of MC activation by neuropeptides such as substance P (SP), corticotropin-releasing hormone (CRH), and neurotensin (NT), and the role of pro-inflammatory cytokines, suggesting a therapeutic effect of the anti-inflammatory cytokines IL-37 and IL-38.
Background: MCs are known to interact with neuropeptides that mediate endothelial cell activation, resulting in central nervous system (CNS) inflammatory disorders. In the brain, MCs interact with neurons causing neuronal excitation with the production of neuropeptides and the release of inflammatory mediators such as cytokines and chemokines. Also, in 1973, Susan Leeman isolated NT for the first time. NT is a 13 amino acid peptide which plays the role of neuromodulator and neurotransmitter in the CNS.
Brain microglia can be activated by neuropeptides, which can also activate mast cells (MCs), leading to pro-inflammatory cytokines, brain disorders, and neuron disorders, an effect that can be inhibited by IL-37 or IL-38.
There are several neuropeptides that can activate cerebral MCs that can produce pathological phenomena. For example, SP is capable of inducing itch due to the interaction of SP with neurokinin-1 receptor (NK1R) on neurons. NT binding its receptor NTR1 of the MC, stimulates the production of cytokines and chemokines through the activation of RAS, which promote the transcription factor AP-1 in the nucleus and, consequently, the production of cytokines/chemokines. Stress-induced NT can mediate neurogenic inflammation in SP-enhanced mice, causing activation and degranulation of MCs via the NK-1 receptor.
The authors report that the neuropeptides substance P, CRH and neurotensin stimulate IL-1, IL-6, and TNF. The inhibition of IL-1 by IL-37 or IL-38 could create new therapeutic possibilities and is a new concept that has not yet been reported in the literature for MCs.
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