Mast cell-neural interactions contribute to pain and itch - PubMed (original) (raw)

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Mast cell-neural interactions contribute to pain and itch

Kalpna Gupta et al. Immunol Rev. 2018 Mar.

Abstract

Mast cells are best recognized for their role in allergy and anaphylaxis, but increasing evidence supports their role in neurogenic inflammation leading to pain and itch. Mast cells act as a "power house" by releasing algogenic and pruritogenic mediators, which initiate a reciprocal communication with specific nociceptors on sensory nerve fibers. Consequently, nerve fibers release inflammatory and vasoactive neuropeptides, which in turn activate mast cells in a feedback mechanism, thus promoting a vicious cycle of mast cell and nociceptor activation leading to neurogenic inflammation and pain/pruritus. Mechanisms underlying mast cell differentiation, activation, and intercellular interactions with inflammatory, vascular, and neural systems are deeply influenced by their microenvironment, imparting enormous heterogeneity and complexity in understanding their contribution to pain and pruritus. Neurogenic inflammation is central to both pain and pruritus, but specific mediators released by mast cells to promote this process may vary depending upon their location, stimuli, underlying pathology, gender, and species. Therefore, in this review, we present the contribution of mast cells in pathological conditions, including distressing pruritus exacerbated by psychologic stress and experienced by the majority of patients with psoriasis and atopic dermatitis and in different pain syndromes due to mastocytosis, sickle cell disease, and cancer.

Keywords: atopic dermatitis; cancer; itch; mast cell; mastocytosis; neurogenic inflammation; pain; pruritus; psoriasis; sickle cell disease.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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Conflict of interest statement

Disclosures

KG is a consultant for Fera Pharmaceuticals LLC and Tau tona Group. ITH has no conflict of interest to declare related to this manuscript.

Figures

Figure 1

Figure 1. Origin and differentiation of mast cells

Mast cells are tissue-resident myeloid cells, which originate from hematopoietic stem cells (HSC) in the bone marrow. HSC differentiate into early or mature myeloid progenitor cells (MPC) in the bone marrow and transmigrate to different tissues via circulation. In the tissues MPCs differentiate into mast cells and undergo maturation. During maturation, remarkable heterogeneity occurs depending upon the tissue, microenvironment, and pathological condition. In the same species, mast cells from different organs may vary significantly. In the same tissue, heterogeneity may occur between the pathological and normal condition.

Figure 2

Figure 2. Different modes of mast cell activation

Mast cell activation involves diverse processes involving the release of mediators and structural alterations for dissemination of mediators and cell-cell communication. The mode of activation is highly heterogeneous and depends upon location and chemical and anatomical stimuli in the surrounding microenvironment and pathological condition.

Figure 3

Figure 3. Activated mast cells surround nerve fibers in the skin of sickle mice

Laser scanning confocal microscopy (LSCM) of 100 um-thick dorsal skin sections immunostained with 1:200 rabbit anti-c-kit (Santa Cruz Biotech., sc-5535), 1:200 goat anti-tryptase (Santa Cruz Biotech., sc-32473), and 1:1000 chicken anti-Neurofilament H-200 (Abcam, ab72996). Sections were subsequently labeled with the following secondary antibodies: 1:400 donkey cy2 anti-rabbit (711-225-152), 1:400 donkey cy3 anti-goat (705-165-147), and 1:400 donkey cy5 anti-chicken (703-175-155) (Jackson Immunoresearch). Z-stacks of 4 um thickness each were sequentially acquired using an Olympus FluoView FV1000 BX2 Upright Confocal microscope at 60× magnification. Rendition of 3D reconstruction of original LSCM image was performed using Imaris 7.5.2 software (Bitplane Inc., Zurich, Switzerland). Image represents reproducible images from 5 different ~5-month old male transgenic HbSS-BERK sickle mice. Note the blue axonal nerve fiber surrounded by degranulating mast cells (green) loaded with tryptase (red). Several degranulating mast cells (red arrow) are nesting in the nerve plexus (blue), which may be responsible for disruption of the nerve plexus observed in this mouse model earlier. In addition to degranulation, mast cells are extending pseudopodia clutching the nerve fiber (white arrow) and interconnecting mast cells around the axon (yellow arrow). Multiple structures appear like vesicle of different sizes (green arrow) suggestive of exosomes (<150 nm), microvesicles (100–1,000 nm), and large oncosomes (1,000–5,000 nm). Thin sprouting nerve fibers are seen emerging between the highly dense degranulating mast cells. This inflammatory pathology caused by mast cell activation may underlie neuropathic pain as a result of neural injury in SCD.

Figure 4

Figure 4. Mast cell extracellular traps (MCETS) surround cutaneous vasculature in sickle mice

Laser scanning confocal microscopy of 100 um-thick dorsal skin sections were immunostained with rabbit anti-Histone H3 (red), a marker of chromatin modification in traps (citrulline R2 + R8 + R17; 1:1000; Abcam, ab5103), goat anti-FcεRI (turquoise), a marker of mast cells, and a rat anti-CD31 (green), a marker of blood vessels (both1:200; Santa Cruz, sc-18916). Secondary antibodies used were from Jackson Immunoresearch: 1:400 donkey cy3 anti-rabbit (711-165-152), 1:400 donkey cy2 anti-goat (705-225-147), and 1:400 donkey cy5 anti-rat (712-175-153). Images were acquired in _z_-sections of 1 um/slice, using an Olympus FluoView FV1000 BX2 Upright Confocal microscope at 240× magnification. Image represents reproducible images from 5 different ~5-month-old male transgenic HbSS-BERK sickle mice. Note red aggregates and spread out arrays (red arrows) exhibiting MCETs due to citrullination of histones shooting out from the turquoise FcεRI-stained mast cells (turquoise arrows). Mast cells in turquoise surround the green blood vessel (green arrow), and their extravasating citrullinated arrays of traps appear to be penetrating into the lumen. Sickle cell disease (SCD) is characterized by vascular dysfunction, vasculopathy, and vascular leakage. This intimate association of degranulating mast cells and MCETs suggest that mast cell activation may contribute to vascular dysfunction in SCD.

Figure 5

Figure 5. Proposed function of mast cells in neurovascular interactions underlying painor itch

Mast cells release a plethora of substances upon activation that can have direct effects on the vasculature, nerve fibers in the periphery, spinal cord, and brain. Inflammatory cytokines, endothelin, histamine, proteases, prostaglandins, and neurotransmitters released from mast cells can directly activate nociceptors or pruriceptors and microglial cells; this contributes to neuronal sensitization and leads to pain or itch. In parallel, these substances influence vascular function by increasing vascular permeability, remodeling, blood flow, and coagulation; these substances also increase inflammation by releasing cytokines and neuropeptides and by recruiting and activating neutrophils and other pro-inflammatory cells. In turn, activated nerve fibers, endothelial cells, and pro-inflammatory cells release several substances including neuropeptides, which may have a paracrine feedback effect on mast cell activation. Many substances released by mast cells may act in an autocrine manner, thus leading to their continuous activation and sustained direct and indirect effects on vascular and nervous systems. Substances, such as neuropeptides released by nerve fibers, increase vascular permeability and plasma extravasation and lead to neurogenic inflammation accompanied by pain or itch. Together, mast cell activation orchestrates a vicious cycle of inflammation, neurogenic inflammation, and pain/itch.

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