Blood-borne donor mast cell precursors migrate to mast cell-rich brain regions in the adult mouse

doi:10.1016/j.jneuroim.2011.09.003

Journal of Neuroimmunology

Volumes 240–241, 15 December 2011, Pages 142-146

https://doi.org/10.1016/j.jneuroim.2011.09.003 Get rights and content

Abstract

Mast cells are hematopoietic immune cells located throughout the body, including within the brain. Reconstitution of mast cell deficient Kit^W-sh/W-sh mice has proven valuable in determining peripheral mast cell function. Here we study the brain mast cell population using a novel method of blood transfusion for reconstitution. We show that blood transfusion results in mast cells of donor origin in the WT mouse, including in the brain where they are restricted to regions bearing host mast cells. In contrast, in Kit^W-sh/W-sh mice, transfusion results in mast cells in the pinna of the ear, but not the brain.

Introduction

Mast cells are hematopoietic immune cells and are located throughout the body, including in the brain. The physiological function of peripheral mast cells has become better understood through reconstitution of these cells in mast cell deficient (Kit^W-sh/W-sh). Peripheral mast cell populations can be partially restored in Kit^W-sh/W-sh mice by intravenous injection of wild-type bone marrow-derived mast cells (BMMCs) (Grimbaldeston et al., 2005, Wolters et al., 2005). The results of such studies implicate peripheral mast cells in host defense and angiogenesis (Mallen-St Clair et al., 2004, Soucek et al., 2007, Liu et al., 2009). While peripheral mast cell reconstitution serves as a powerful tool to examine mast cell biology, the efficacy of central mast cell reconstitution is not clear. BMMCs injected into mast cell deficient Kit^W-sh/W-sh mice do not populate the brain (Grimbaldeston et al., 2005, Bennett et al., 2009). In rat, mature donor peritoneal mast cells (PMCs) injected intravenously cross the blood–brain barrier into the brain parenchyma within 1 h (Silverman et al., 2000).

In normal physiology, mature mast cells are not found in the blood. Rather, mast cell precursors circulate in the blood, enter tissues and mature in their local microenvironment (Kitamura and Fujita, 1989, Chen et al., 2005). In the present study, we explore the possibility of adoptive transfer of mast cells by transplanting their precursors via blood transfusion into wild-type (WT) and mast cell deficient Kit^W-sh/W-sh mice using blood transfusion from Okabe mice. We show that mature donor-derived mast cells are found in WT mice within 2 weeks of transfusion, and remain resident there for at least 12 weeks: Their distribution coincides with the localization of resident host mast cells. In contrast, donor mast cells were not observed in Kit^W-sh/W-sh host brain, but were seen in the pinna of the ear.

Section snippets

Animals

Three lines of mice (Jackson Laboratories, Bar Harbor, ME) were used in these studies: (1) C57BL/6 male WT, (2) mast cell deficient C57BL/6-Kit^W-sh/W-sh mice (B6.Cg-Kit^W-sh/HNihrJaeBsmJ), and (3) Okabe mice (C57BL/6-Tg (CAG-EGFP) 1Osb/J) that express green fluorescent protein (GFP) in all tissues except erythrocytes and hair (Okabe et al., 1997). Mice were housed in standard laboratory cages with ad libitum food and water in a 12:12 light–dark cycle at 22 ± 1 °C. All procedures were approved by

Blood transfusion results in donor mast cells in the brain of WT, but not Kit^W-sh/W-sh mice

Host mast cells, identified by avidin and lack of GFP, were localized in the diencephalic and hippocampal parenchyma as well as choroid plexus and meninges of WT mice (Fig. 1a). Donor cells identified by expression of GFP, were found throughout the brain of WT mice following whole blood transfusion (Fig. 1a), but not in saline-injected WT controls (Fig. 1b). Donor mast cells, identified by expression of both GFP avidin, were found in the brains of WT mice from 2 to 12 weeks following blood

Discussion

Mast cells leave the bone marrow and circulate in the blood in an immature state before entering tissue where they mature (Kitamura and Fujita, 1989). Using whole blood, the present results show that donor mast cells from Okabe mice occur in the brain of WT mice as early as 2 weeks, and as late as 12 weeks following transfusion. This is the first demonstration of whole blood transfusion as a method of adoptive transfer to introduce donor mast cells into host tissue, and may prove useful in

Acknowledgments

We'd like to thank Drs. Joseph LeSauter and Matthew Butler for their help with this project. Funding sources: F31 NIMH 084384 (to KMN), NSF IOS 05-54514 and R21 NIMH 067782 (to RS).

References (25)

L. Asarian et al.
Stimuli from conspecifics influence brain mast cell population in male rats
Horm. Behav.
(2002)
M.R. Blanchet et al.
CD34 facilitates the development of allergic asthma
Blood
(2007)
E. Drew et al.
CD34 is a specific marker of mature murine mast cells
Exp. Hematol.
(2002)
F. Geissmann et al.
Blood monocytes consist of two principal subsets with distinct migratory properties
Immunity
(2003)
M.A. Grimbaldeston et al.
Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo
Am. J. Pathol.
(2005)
M. Lambracht-Hall et al.
Migration of mast cells in the developing rat brain
Brain Res. Dev. Brain Res.
(1990)
G. Nilsson et al.
Mast cell migratory response to interleukin-8 is mediated through interaction with chemokine receptor CXCR2/Interleukin-8RB
Blood
(1999)
M. Okabe et al.
‘Green mice’ as a source of ubiquitous green cells
FEBS Lett.
(1997)
J. Sawada et al.
Nerve growth factor functions as a chemoattractant for mast cells through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways
Blood
(2000)
T.C. Theoharides et al.
Novel therapeutic targets for autism
Trends Pharmacol. Sci.
(2008)

J.L. Bennett et al.

Bone marrow-derived mast cells accumulate in the central nervous system during inflammation but are dispensable for experimental autoimmune encephalomyelitis pathogenesis

J. Immunol.

(2009)

E. Brzezinska-Blaszczyk et al.

Tumor necrosis factor (TNF) is a potent rat mast cell chemoattractant

J. Interferon Cytokine Res.

(2007)

Cited by (16)

Children with allergic rhinitis and a risk of epilepsy: A nationwide cohort study
2020, Seizure
Citation Excerpt :
They are first responders and are regarded as the immune gate to the brain [24,25], acting as catalyst and recruiters to initiate, magnify, and prolong immune and nervous responses in the brain upon activation [14–17,24–29]. Mast cells produce a plethora of vasodilatory and proinflammatory mediators upon stimulation by allergic triggers, including histamine, serotonin, and cytokines, thereby eliciting a cascade of inflammatory events within the brain, and thus focal brain inflammation could then contribute to or exacerbate seizures [14–17,24–29]. It is suggested that mast cells are present in the brain as resident cells or migratory cells from the periphery [27–29], resident mast cells of the brain therefore become activated and/or peripheral mast cells become recruited into the brain upon allergic responses, resulting in focal brain inflammation and that this could become an epileptogenic site [24–27].
Little is known about whether allergic disease is associated with a subsequent increased risk of childhood-onset epilepsy. We used a large, population-based cohort study to examine whether children with antecedent allergic rhinitis (AR) were associated with a subsequent increased risk of epilepsy.
This retrospective population-based cohort study was conducted by using data from the 2000–2012 Taiwan’s National Health Insurance Research Database. We enrolled 67,537 children aged 0–18 years diagnosed with AR and 67,537 age- and gender-matched children without the diagnosis of AR. The incidence rate (per 10,000 person-years) of epilepsy was calculated. We used Cox proportional hazards regression analysis to estimate hazard ratios (HRs) and 95 % confident interval (CI).
Of the 135,074 children included in the analyses, those with AR had a higher incidence rate of epilepsy (6.84 versus 3.95 per 10,000 person-years, p < 0.001) and an earlier age at diagnosis of epilepsy than those without AR [8.54 (4.90) versus 9.33 (5.40) years, p = 0.03)]. The Kaplan-Meier survival analysis demonstrated that the children with AR had a higher likelihood of developing epilepsy than those without AR (p < 0.001). After adjusting for confounding factors in multivariate model, children with AR had a 76 % increased risk of epilepsy (HR 1.76, 95 % CI 1.51–2.04) than those without AR. Boys had a 21 % increased risk of epilepsy (HR 1.21, 95 % CI 1.05–1.40) than girls.
These results suggest that children with AR were associated with an increased subsequent risk of epilepsy.
Mast cells in neuroinflammation and brain disorders
2017, Neuroscience and Biobehavioral Reviews
Citation Excerpt :
Already during development, mast cells enter the brain by migration along the blood vessels (Skaper et al., 2014a). Also, mature mast cells are capable of migrating from the periphery to the brain (Nautiyal et al., 2011; Silverman et al., 2000). Most mast cells reside on the abluminal side of the blood vessels, where they are able to communicate with neurons, glial cells and the endothelial cells (ECs) of the extracellular matrix (ECM) (Dong et al., 2014a; Silver and Curley, 2013).
It is well recognized that neuroinflammation is involved in the pathogenesis of various neurodegenerative diseases. Microglia and astrocytes are major pathogenic components within this process and known to respond to proinflammatory mediators released from immune cells such as mast cells. Mast cells reside in the brain and are an important source of inflammatory molecules. Mast cell interactions with glial cells and neurons result in the release of mediators such as cytokines, proteases and reactive oxygen species. During neuroinflammation, excessive levels of these mediators can influence neurogenesis, neurodegeneration and blood-brain barrier (BBB) permeability. Mast cells are considered first responders and are able to initiate and magnify immune responses in the brain. Their possible role in neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and autism has gained increasing interest. We discuss the possible involvement of mast cells and their mediators in neurogenesis, neurodegeneration and BBB permeability and their role in neuronal disorders such as cerebral ischemia, traumatic brain injury, neuropathic pain, multiple sclerosis, Alzheimer’s disease, migraine, autism, and depression.
The mast cell stabilizer sodium cromoglycate reduces histamine release and status epilepticus-induced neuronal damage in the rat hippocampus
2015, Neuropharmacology
Citation Excerpt :
The release of different factors from mast cells and other conditions such as cross-linking and activation of the high-affinity immunoglobulin E receptor (αFcεR1), complement factors (Turner and Kinet, 1999), hyperthermia, hypoxia, and substance P (Jin et al., 2009; Bleck, 2009; Liu et al., 1999) may induce direct tissue damage as consequence of the status epilepticus. Future studies should be designed to support the notion that perivascular mast cells are the first responders to the status epilepticus with subsequent damage of the BBB and migration of cells from blood to brain, including peripheral mast cells (Silverman et al., 2000; Nautiyal et al., 2011). Alternatively, neurons could be responsible for the release of histamine during status epilepticus (Zant et al., 2012).
Experiments were designed to evaluate changes in the histamine release, mast cell number and neuronal damage in hippocampus induced by status epilepticus. We also evaluated if sodium cromoglycate, a stabilizer of mast cells with a possible stabilizing effect on the membrane of neurons, was able to prevent the release of histamine, γ-aminobutyric acid (GABA) and glutamate during the status epilepticus. During microdialysis experiments, rats were treated with saline (SS-SE) or sodium cromoglycate (CG-SE) and 30 min later received the administration of pilocarpine to induce status epilepticus. Twenty-four hours after the status epilepticus, the brains were used to determine the neuronal damage and the number of mast cells in hippocampus. During the status epilepticus, SS-SE group showed an enhanced release of histamine (138.5%, p = 0.005), GABA (331 ± 91%, p ≤ 0.001) and glutamate (467%, p ≤ 0.001), even after diazepam administration. One day after the status epilepticus, SS-SE group demonstrated increased number of mast cells in Stratum pyramidale of CA1 (88%, p < 0.001) and neuronal damage in dentate gyrus, CA1 and CA3. In contrast to SS-SE group, rats from the CG-SE group showed increased latency to the establishment of the status epilepticus (p = 0.048), absence of wet-dog shakes, reduced histamine (but not GABA and glutamate) release, lower number of mast cells (p = 0.008) and reduced neuronal damage in hippocampus. Our data revealed that histamine, possibly from mast cells, is released in hippocampus during the status epilepticus. This effect may be involved in the subsequent neuronal damage and is diminished with sodium cromoglycate pretreatment.
Amyloid Beta Peptides Lead to Mast Cell Activation in a Novel 3D Hydrogel Model
2023, International Journal of Molecular Sciences
Mast cell-mediated immune regulation in health and disease
2023, Frontiers in Medicine
Mast cells and histamine are involved in the neuronal damage observed in a quinolinic acid-induced model of Huntington's disease
2022, Journal of Neurochemistry

View all citing articles on Scopus

View full text

Short communicationBlood-borne donor mast cell precursors migrate to mast cell-rich brain regions in the adult mouse

Abstract

Introduction

Section snippets

Animals

Blood transfusion results in donor mast cells in the brain of WT, but not KitW-sh/W-sh mice

Discussion

Acknowledgments

Horm. Behav.

Blood

Exp. Hematol.

Immunity

Am. J. Pathol.

Brain Res. Dev. Brain Res.

Blood

FEBS Lett.

Blood

Trends Pharmacol. Sci.

Bone marrow-derived mast cells accumulate in the central nervous system during inflammation but are dispensable for experimental autoimmune encephalomyelitis pathogenesis

J. Immunol.

Tumor necrosis factor (TNF) is a potent rat mast cell chemoattractant

J. Interferon Cytokine Res.

Short communication
Blood-borne donor mast cell precursors migrate to mast cell-rich brain regions in the adult mouse

Blood transfusion results in donor mast cells in the brain of WT, but not Kit^W-sh/W-sh mice