Brain mast cells link the immune system to anxiety-like behavior

Nautiyal, Katherine M.; Ribeiro, Ana C.; Pfaff, Donald W.; Silver, Rae

doi:10.1073/pnas.0809479105

Cited by 160 publications

(128 citation statements)

References 75 publications

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“…Kit W-sh/W-sh mice show a greater anxiety-like phenotype than WT controls. 71 Located in close proximity with the blood-brain barrier, MCs represent early responders to cerebral ischemia and potent inflammatory effector cells. 72 MCs may even modulate tumor metastasization into the brain.…”

Section: Discussionmentioning

confidence: 99%

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Piconese

Costanza

Musio

et al. 2011

Laboratory Investigation

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Mast cell (MC)-deficient c-Kit mutant Kit W/W-v mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. To further investigate the role of MCs in EAE, we took advantage of a recently characterized model of MC deficiency, Kit W-sh/W-sh . Surprisingly, we observed that myelin oligodendrocyte glycoprotein (MOG) 35-55 -induced chronic EAE was exacerbated in Kit W-sh/W-sh compared with Kit þ / þ mice. Kit W-sh/W-sh mice showed more inflammatory foci in the central nervous system (CNS) and increased T-cell response against myelin. To understand whether the discrepant results obtained in Kit W-sh/W-sh and in Kit W/W-v mice were because of the different immunization protocols, we induced EAE in these two strains with varying doses of MOG and adjuvants. Although Kit W-sh/W-sh mice exhibited exacerbated EAE under all immunization protocols, Kit W/W-v mice were protected from EAE only when immunized with high, but not low, doses of antigen and adjuvants. Kit W-sh/W-sh mice reconstituted systemically, but not in the CNS, with bone marrow-derived MCs still developed exacerbated EAE, indicating that protection from disease could be exerted by MCs mainly in the CNS, and/or by other cells possibly dysregulated in Kit W-sh/W-sh mice. In summary, these data suggest to reconsider MC contribution to EAE, taking into account the variables of using different experimental models and immunization protocols. MCs are key factors in IgE-associated immediate hypersensitivity reactions, during which they release a wide spectrum of inflammatory mediators in response to IgE and antigen (Ag) stimulation. 1 However, recent findings have pointed out that MCs may exert also important effector and/or immunomodulatory functions in other physiopathological conditions as venom detoxification, pathogen clearance, tumor growth, contact hypersensitivity, allograft acceptance and autoimmunity. 2 Most of these studies have assessed the in vivo role of MCs by the use of mouse models carrying spontaneous mutations in c-Kit receptor (WBB6F 1 -Kit W/W-v or C57BL/6-Kit W-sh/W-sh mice) or c-Kit ligand (WCB6F 1 -Kitl Sl /Kitl Sl-d ), which show severe deficiency of MC populations. 3,4 MCs may either enhance or suppress the inflammation associated to different types of autoimmune diseases. MC-deficient Kit W/W-v and Kitl Sl/Sl-d mice are protected from autoantibodymediated models of rheumatoid arthritis and bullous pemphigoid, inflammatory disorders affecting, respectively, the joint and the skin. Reconstitution of Kit W/W-v mice with bone marrow derived, in vitro cultured MCs (BMMCs) restores complete disease susceptibility in both conditions, thus indicating a proinflammatory role of these cells in such diseases. 5,6 Conversely, MCs seem to exert a protective function in experimental autoimmune glomerulonephritis, by limiting clinical and histological glomerular pathology and mortality. 7,8 However, recent work has shown that, unlike Kit W/W-v , Ki...

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Section: Discussionmentioning

confidence: 99%

Exacerbated experimental autoimmune encephalomyelitis in mast-cell-deficient KitW-sh/W-sh mice

Piconese

Costanza

Musio

et al. 2011

Laboratory Investigation

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“…These observations suggest that specific interactions between the nervous and immune systems contribute to normal brain function. Mast cells, an immune cell classically associated with allergic responses, are also important for supporting adult neurogenesis (Nautiyal et al 2008(Nautiyal et al , 2012. Mast cells are resident in and around the hippocampus and secrete serotonin.…”

Section: Brain Support By the Peripheral Immune Systemmentioning

confidence: 99%

“…Mast cells are resident in and around the hippocampus and secrete serotonin. From this location they appear to play a role in maintaining the neurogenic niche, since treatment with fluoxetine, a selective inhibitor of serotonin reuptake, abolishes the differences in neurogenesis between mice deficient in mast cells and their heterozygotic littermates (Nautiyal et al 2008).…”

Section: Brain Support By the Peripheral Immune Systemmentioning

confidence: 99%

Learning and memory … and the immune system

2013

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The nervous system and the immune system are two main regulators of homeostasis in the body. Communication between them ensures normal functioning of the organism. Immune cells and molecules are required for sculpting the circuitry and determining the activity of the nervous system. Within the parenchyma of the central nervous system (CNS), microglia constantly monitor synapses and participate in their pruning during development and possibly also throughout life. Classical inflammatory cytokines, such as interleukin (IL)-1b and tumor necrosis factor (TNF), are released during neuronal activity and play a crucial role in regulating the strength of synaptic transmission. Systemically, proper functioning of the immune system is critical for maintaining normal nervous system function. Disruption of the immune system functioning leads to impairments in cognition and in neurogenesis. In this review we provide examples of the communication between the nervous and the immune systems in the interest of normal CNS development and function.

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“…For example, histamine has both anxiolytic and anxiogenic effects, with opposing roles attributed to H1 versus H2 receptors [61,62]. Serotonin functions both as a transmitter affecting aggression, appetite, and mood, and as a trophic factor influencing neurogenesis to affect emotionality and memory [62].…”

Section: Vulvar Vestibulitis-provoked Vestibulodyniamentioning

confidence: 99%