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Comparative Study
, 22 (9), 2238-48

Central Nervous System Neurons Acquire Mast Cell Products via Transgranulation

Affiliations
Comparative Study

Central Nervous System Neurons Acquire Mast Cell Products via Transgranulation

M Wilhelm et al. Eur J Neurosci.

Abstract

Resting and actively degranulating mast cells are found on the brain side of the blood-brain barrier. In the periphery, exocytosis of mast cell granules results in the release of soluble mediators and insoluble granule remnants. These mast cell constituents are found in a variety of nearby cell types, acquired by fusion of granule and cellular membranes or by cellular capture of mast cell granule remnants. These phenomena have not been studied in the brain. In the current work, light and electron microscopic studies of the medial habenula of the dove brain revealed that mast cell-derived material can enter neurons in three ways: by direct fusion of the granule and plasma membranes (mast cell and neuron); by capture of insoluble granule remnants and, potentially, via receptor-mediated endocytosis of gonadotropin-releasing hormone, a soluble mediator derived from the mast cell. These processes result in differential subcellular localization of mast cell material in neurons, including free in the neuronal cytoplasm, membrane-bound in granule-like compartments or in association with small vesicles and the trans-Golgi network. Capture of granule remnants is the most frequently observed form of neuronal acquisition of mast cell products and correlates quantitatively with mast cells undergoing piecemeal degranulation. The present study indicates that mast cell-derived products can enter neurons, a process termed transgranulation, indicating a novel form of brain-immune system communication.

Figures

Fig. 1
Fig. 1
Mast cells and neurons in the medial habenula as visualized in 1-μm plastic sections stained with toluidine blue, pH 11. Mast cells are distinguished from neurons by their large secretory granules and heterochromatic nucleus (white asterisk). Nuclei (nu) of neighboring neurons (N) are euchromatic. (A) The mast cell cytoplasm is filled with intensely stained granules. Those that are intact are blue to purple. Small regions of the cytoplasm are pink and are sites of granules undergoing degranulation. In the neighboring neurons, N1 and N2, patches of pink are present in the cytoplasm (arrowhead). In N3 a small cluster of stained granules is present (arrow). N1 and N2 correspond to the electron micrograph in Fig. 3. (B) In this instance the neuronal nucleus contains pink material apparently in a small sac (arrow); this cell is cut through the nucleolus (arrowhead). This cell is also shown in the electron micrograph in Fig. 4. bv, blood vessel.
Fig. 2
Fig. 2
Two examples of transcytosis via transcellular exocytosis. (A) In this electron micrograph a portion of a mast cell is shown with its electron-dense granules (white G) and a particulate granule (P). The arrows indicate fine mast cell filopodia in contact with a small dendrite (D). The membrane of the particulate granule (P) and plasma membranes of both the mast cell and dendrite have fused. Small particles, morphologically similar to those in the particulate granule, are in the dendritic cytoplasm at the site of fusion (arrowheads). m, myelinated axon; g, electron-lucent granule; nu, nucleus. (B) As in A mast cell filopodia (arrow) come in contact with a neuron (Na) and small particles of the same size and morphology as those in the granule (P) are present in the neuronal cytoplasm (arrowheads). Another granule (G) makes close contact with an adjacent neuron (Nb). In both A and B the granule fusing with the neuron is part of a fusion chamber in which one or more granules have fused with the granule which is at the plasma membrane (* in both). (C) A higher magnification of the contact zone in B. The mast cell particles appear as two separate streams (arrowheads). Arrow indicates a mast cell filopodium. (D) This is the serial section to C. Within the intervening ~70 nm the fusion point has closed and mast cell filopodia (arrow) are inserted between the two cell types. (E) A higher magnification of the granule marked G in B. Note that it is apposed to the neuronal plasma membrane but its own membrane is intact. There is no evidence of mast cell material in the neuron in this or the next serial section. (F) Arrow points to mast cell filopodia.
Fig. 3
Fig. 3
Localization of mast cell granule remnants in neighboring neurons. (A) Low magnification of a mast cell (MC) and adjacent neurons. Note the heterogeneity in size, shape and electron density of the granules that fill the mast cell cytoplasm. The arrows indicate electron-lucent, particle-filled granules characteristic of ongoing or recovery from exocytosis. Two neurons (N1 and N2; as shown in Fig. 1) contain mast cell granules (* and **, respectively). (B) A higher magnification of the granule remnants in A designated with *. In this section, two of the four contiguous remnants (*) (as identified in a set of serial sections, not shown) are seen. The granular material is enclosed by membrane (arrow). (C) A higher magnification of the granule remnant (**) in N2. This section is separated from that shown in A by ~200 nm. The remnant is composed of two chambers, one swollen and devoid of particles (g) and a compartment which retains particulate (**) and vesicular substructure (arrow). The second compartment is in contact with the outer nuclear envelope (arrowhead). nu, nucleus.
Fig. 4
Fig. 4
In this example of transgranulation, a multicompartment, particle-containing granule remnant (G) is present within the neuronal nucleus (nu) (neuron in Fig. 1B). The arrows indicate the membrane associated with this granule remnant. A small portion of a mast cell (MC), as identified by its granules (white asterisk), borders the neuron. *, nucleolus; C, neuronal cytoplasm.
Fig. 5
Fig. 5
Two examples of mast cell granules in pre-synaptic elements (as defined by the clustering of synaptic vesicles, arrowheads). (A) The inclusion is an expanded remnant (G) similar to the particulate granules in the neighboring mast cell (Gmc). Also note a granule remnant (g) external to either cell and surrounded by filopodia (arrows). In B a pre-synaptic terminal contains a granule (*) with a well-defined membrane and vesicular interior (*). An externalized granule (g) is present, surrounded by mast cell filopodia (arrows). Ax, axon; As, astrocyte; d, dendrite; MC, mast cell; m, mitochondrion.
Fig. 6
Fig. 6
Examples of granules in mast cell cytoplasmic extensions. (A) The granule (G) is isolated from the mast cell cytoplasm by several layers of filopodia (*, first layer; arrow, multiple layers). The cell in B is in the pia and electron-dense granules (white asterisk) are frequently present in the small cellular extensions. This mast cell is primarily filled with electron-lucent granules associated with piecemeal degranulation (G). MC, mast cell; nu, nucleus.
Fig. 7
Fig. 7
Ultrastructural immunocytochemical evidence for mast cell-derived gonadotropin-releasing hormone (GnRH) in neurons. (A) 3,3′ diaminobenzidine (DAB), used to detect sites of antibody binding, forms a flocculent deposit (which can obscure finer ultrastructural detail) in some (white arrow) but not all granules within the mast cell. DAB deposits are also present in two adjacent neurons (N1 and N2; arrowheads). There are multiple layers of mast cell filopodia cut in both longitudinal and cross section (double arrows). Some of these are associated with DAB deposits (long arrows). (B) In this plane of section the mast cell (MC) has few granules. Within the neuron (N), small deposits of immunoreactive material are found associated with vesicles (arrows). Some of these vesicles are close to the Golgi apparatus (g). DAB is also associated with the surface of filopodia (arrowhead). Double arrows indicate the characteristic multiple filopodial layers of the MC.

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