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Martin Metz

Publications and source records attributed to Martin Metz.

11 recordsLinked to original sources
PubMed2006

Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses.

Mast cells are best known as critical effector cells in anaphylaxis and other examples of IgE-associated immediate hypersensitivity reactions. However, mast cells also can contribute to the development of the late-phase responses that occur in some sensitized subjects hours after initial exposure to specific antigen, and can promote many of the features of chronic allergic inflammation, including tissue remodeling and functional changes in the affected organs. In addition to such effector cell functions in IgE-associated immune responses, recent evidence indicates that mast cells can importantly influence the sensitization phase of at least some acquired immune responses, and can contribute to the pathology of autoimmune disorders and to the expression of peripheral tolerance.

Animals↗
PubMed2006

Mast cells can enhance resistance to snake and honeybee venoms.

Snake or honeybee envenomation can cause substantial morbidity and mortality, and it has been proposed that the activation of mast cells by snake or insect venoms can contribute to these effects. We show, in contrast, that mast cells can significantly reduce snake-venom-induced pathology in mice, at least in part by releasing carboxypeptidase A and possibly other proteases, which can degrade venom components. Mast cells also significantly reduced the morbidity and mortality induced by honeybee venom. These findings identify a new biological function for mast cells in enhancing resistance to the morbidity and mortality induced by animal venoms.

Animals↗
PubMed2006

Skin mast cells control T cell-dependent host defense in Leishmania major infections.

Mast cells (MCs) initiate protective immunity against bacteria. Here we demonstrate that MCs also contribute to the control of parasitic skin infections by Leishmania major. L. major-infected MC-deficient Kit(W)/Kit(W-v) mice developed markedly larger skin lesions than did normal Kit+/+ mice (>2-fold), and cutaneous reconstitution with MCs resulted in normalization of lesion development. Kit(W)/Kit(W-v) lesions contained significantly more parasites, and infections resulted in enhanced spreading of parasites to the spleens as compared to controls. In addition, recruitment of proinflammatory neutrophils, macrophages, and dendritic cells (DCs) in infected mice was MC dependent. In the absence of MCs, reduced numbers of lesional DCs were associated with decreased production of Th1-promoting interleukin (IL)-12. Antigen-specific T cell priming was delayed in Kit(W)/Kit(W-v) mice and cytokine responses were skewed towards Th2. Notably, local skin MC reconstitution at sites of infection was sufficient for the induction of systemic protection. Thus, MC-mediated control of L. major infections is not limited to the induction of local inflammation. Instead, MCs contribute significantly to local DC recruitment, which mediates protective immunity. These findings extend the view of MCs as salient sentinels of innate immunity to complex host defense reactions against intracellular pathogens.

Animals↗
PubMed2006

Inflammatory murine skin responses to UV-B light are partially dependent on endothelin-1 and mast cells.

Endothelin (ET-1) has been shown to crucially contribute to UV-induced skin responses such as tanning. To test whether ET-1 is also involved in early cutaneous reactions to UV, we assessed ET-1 skin levels in UV-irradiated mice. In correlation with the levels of UV-induced skin inflammation, ET-1 concentrations increased substantially and continually. Moreover, blocking of ET-1 receptors (ETA) resulted in significantly decreased cutaneous inflammation following UV irradiation. When we assessed skin responses to ET-1 injections, we observed prominent mast cell degranulation and mast cell-dependent inflammation. Since mast cells also critically contributed to UV-induced inflammation, we determined the ET-1-dependent inflammatory response to UV in the absence and presence of these cells. Interestingly, ETA blockade did not decrease UV-induced inflammation in mast cell-deficient mice, unless these mice had been adoptively transferred with mast cells before irradiation. This indicates that skin inflammation due to UV irradiation is caused in part by ET-1 acting on skin mast cells.

Animals↗
PubMed2005

TLR3-induced activation of mast cells modulates CD8+ T-cell recruitment.

Mast cells play an important role in host defense against various pathogens, but their role in viral infection has not been clarified in detail. dsRNA, synthesized by various types of viruses and mimicked by polyinosinic-polycytidylic acid (poly(I:C)) is recognized by Toll-like receptor 3 (TLR3). In this study, we demonstrate that poly(I:C) injection in vivo potently stimulates peritoneal mast cells to up-regulate a number of different costimulatory molecules. Therefore, we examined the expression and the functional significance of TLR3 activation in mast cells. Mast cells express TLR3 on the cell surface and intracellularly. After stimulation of mast cells with poly(I:C) and Newcastle disease virus (NDV), TLR3 is phosphorylated and the expression of key antiviral response cytokines (interferon beta, ISG15) and chemokines (IP10, RANTES) is upregulated. Interestingly, mast cells activated via TLR3-poly(I:C) potently stimulate CD8+ T-cell recruitment. Indeed, mast-cell-deficient mice (KitW/KitW-v) given an intraperitoneal injection of poly(I:C) show a decreased CD8+ T-cell recruitment, whereas granulocytes normally migrate to the peritoneal cavity. Mast-cell reconstitution of KitW/KitW-v mice normalizes the CD8+ T-cell influx. Thus, mast cells stimulated through engagement of TLR3 are potent regulators of CD8+ T-cell activities in vitro and in vivo.

Animals↗
PubMed2005

The status quo and quo vadis of mast cells.

Mast cells (MCs) have been intensely investigated over the past two decades, e.g. the numbers of PubMed-listed reports on MCs have steadily increased and doubled over the past twenty years. Surprisingly, many recent findings that have fundamentally changed our understanding of MC biology and functions have yet to be sufficiently recognized by scientists interested in cutaneous biology and clinical dermatologists. The aim of this study is to review recent hallmark contributions to the field of MC research, to outline the development of our current knowledge of MCs, and to predict the outcome of future MC research efforts. The development of straightforward rodent in vivo models has allowed for the identification and characterization of various novel MC functions. MC effects are not limited to the induction of pathology, but can serve important functions in maintaining health and preventing disease. Attempts to better define the role of MCs in the human system may lead to novel strategies for treating inflammatory disorders and could eventually allow us to utilize MCs for improving responses to environmental danger signals.

Animals↗
PubMed2004

Mast cells promote homeostasis by limiting endothelin-1-induced toxicity.

Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity. ET-1 has been implicated in diverse physiological or pathological processes, including the vascular changes associated with sepsis. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood. Both the pathology associated with certain allergic and autoimmune disorders, and optimal host defence against bacterial and parasitic infections are mediated by mast cells. In vitro, mast cells can produce ET-1 (ref. 11), undergo ET-1-dependent and endothelin-A receptor (ET(A))-dependent activation, and release proteases that degrade ET-1 (ref. 14). Although the potential relationships between mast cells and the ET-1 system thus may be complex, the importance of interactions between ET-1 and mast cells in vivo is obscure. Here we show that ET(A)-dependent mast-cell activation can diminish both ET-1 levels and ET-1-induced pathology in vivo, and also can contribute to optimal survival during acute bacterial peritonitis. These findings identify a new biological function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.

Animals↗
PubMed2004

Neurotrophin-3 regulates mast cell functions in neonatal mouse skin.

Nerve growth factor (NGF) has long been recognized as an important mast cell (MC) growth factor. To explore whether other neurotrophins (NTs) of the NGF family, which are widely expressed in mouse skin, affect the numbers and/or functions of MCs we examined the effects of NT-3 on neonatal skin MCs. We demonstrate that TrkC, the high affinity NT-3 receptor, is expressed by virtually all neonatal skin MCs in C57BL/6 mice, which indicates that MCs can respond to NT-3. Skin of neonatal and early postnatal NT-3-overexpressing mice (promoter: K14) displayed significantly and up to twofold increased numbers of MCs during the first 20 days after birth, as compared to wild-type mice. To check whether this increase in MC numbers in NT-3 transgenic mice reflects a higher rate of proliferation, we performed immunohistochemistry, which revealed that only 1-2% of all skin MCs both in NT-3-overexpressing and in wild-type controls showed Ki-67-positive nuclei, suggesting that the observed differences in the number of MCs do not reflect a higher rate of MC proliferation. Additionally, we show that the effect of NT-3 on the number of MCs is most likely to be stem cell factor (SCF)-independent, because NT-3 significantly downregulates secretion of SCF-protein in cultured dermal fibroblasts, as assessed by enzyme-linked immunosorbent assay. Numbers of skin MCs in neonatal TrkC-deficient mice were found to be modestly reduced, as compared to wild-type mice, indicating that NT-3 can modulate the number of MCs directly via TrkC, although TrkC does not seem to be essential for the number of basal MCs. To further analyze the effects of NT-3 on MCs, we stimulated skin organ culture of early postnatal C57BL/6 mouse skin with 5-50 ng/ml NT-3, which induced a significant increase in MC degranulation, as visualized by Giemsa staining. However, stimulation of isolated neonatal dermal skin MCs with NT-3 in vitro failed to result in MC activation, as measured by serotonin release. Our data suggest a role for NT-3 in the maturation of MCs, such as a TrkC-mediated stimulation of the differentiation of pre-existing, less mature MCs and/or by enhancing the migration of circulating MC precursors into the skin.

Animals↗
PubMed2003

Critical role of IL-10 in the induction of low zone tolerance to contact allergens.

The development and mechanisms of tolerance to allergens are poorly understood. Using the murine low zone tolerance (LZT) model, where contact hypersensitivity (CHS) is prevented by repeated topical low-dose applications of contact allergens, we show that LZT induction is IL-10 dependent. IL-10 is required for the generation of LZT effector cells, that is, CD8+ regulatory T cells. Only T cells from tolerized IL-10+/+ mice or IL-10-/- mice reconstituted with IL-10 during LZT induction adoptively transferred LZT to naive mice and prevented CHS, whereas T cells from IL-10-/- mice failed to do so. The IL-10 required for normal LZT development is derived from lymph node CD4+ T cells, the only skin or lymph node cell population found to produce relevant amounts of IL-10 after tolerization. CD4+ T cells derived from IL-10+/+ mice, but not from IL-10-/- mice, allowed the induction of LZT in adoptively transferred T cell-deficient mice. Interestingly, IL-10 injections during tolerization greatly enhanced LZT responses in normal mice. Thus, the generation of CD8+ LZT effector T cells by CD4+ regulatory T cells via IL-10 may be a promising target of strategies aimed at preventing contact allergies and other harmful immune responses.

Adoptive Transfer↗
PubMed2002

Early macrophage influx to sites of cutaneous granuloma formation is dependent on MIP-1alpha /beta released from neutrophils recruited by mast cell-derived TNFalpha.

Macrophages (MPhi) play a crucial role in the development of cutaneous granulomas (CGs) initiated by foreign bodies or invasive microorganisms. However, little is known about how MPhi are recruited to sites of CG formation. To test whether mast cells (MCs) contribute to early MPhi recruitment to developing granulomas, CGs were induced in MC-deficient Kit(W)/Kit(W-v) mice by injection of polyacrylamide gel (PAG). Kit(W)/Kit(W-v) mice as well as mice deficient in the MC product TNFalpha exhibited markedly reduced MPhi numbers in CGs. MPhi recruitment was restored in Kit(W)/Kit(W-v) mice reconstituted with MCs from Kit(+/+) or TNFalpha(+/+), but not from TNFalpha(-/-) mice. MC-TNFalpha-dependent MPhi influx required prior recruitment of MIP-1alpha/beta-producing neutrophils (PMNs), as PMN depletion before induction of CGs completely inhibited MPhi influx, which was restored after reconstitution with PMN supernatants. These findings indicate that MPhi recruitment to cutaneous PAG- induced granulomas is the result of a sequence of inflammatory processes initiated by MC-derived TNFalpha followed by PMN influx and MIP-1a/beta release.

Animals↗