Pulmonary Responses to Stachybotrys chartarum and Its Toxins: Mouse Strain Affects Clearance and Macrophage Cytotoxicity

Lichtenstein, Jamie H. Rosenblum; Molina, Ramon M.; Donaghey, Thomas C.; Amuzie, Chidozie; Pestka, James J.; Coull, Brent A.; Brain, Joseph D.

doi:10.1093/toxsci/kfq104

Cited by 23 publications

(10 citation statements)

References 54 publications

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“…Strain-dependent differences in the macrophage immune responses to bacterial, parasitic or fungal infections most likely reflecting differences in genetic predisposition of these cells have been reported before (Lichtenstein et al 2010; Sun et al 2011; Vecchio et al 2010). Since microglia share many similarities with macrophages, it is reasonable to expect that microglial properties would also be strain-dependent.…”

Section: Discussionsupporting

confidence: 51%

Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice

Nikodémová

Watters

2011

Neuroscience

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Neuroinflammation mediated by microglia is a pathological hallmark of many CNS disorders. Cell lines derived from inbred C57Bl/6 and outbred ICR/CD1 mice (BV2 and N9 respectively), are often used to study microglial inflammatory activities. Although many studies demonstrate different responses of these cell lines to the same stimulus, no comparisons have been done in vivo. Because inbreeding reduces resistance to pathogens and parasites, we hypothesized that microglia from outbred ICR/CD1 mice would have a stronger response to centrally administered LPS than microglia from inbred C57Bl/6 mice. The evaluation of gene expression in freshly-isolated CD11b+ cells from brain revealed that microglia from ICR/CD1 mice were more pro-inflammatory than those from C57Bl/6 mice, although these differences did not appear to result from alterations in the expression levels of the LPS receptors TLR4 or CD14. Notably, the timing of inflammatory gene expression did not correlate with CD11b+ cell proliferation/infiltration. The highest expression of TNFα, IL-6 and iNOS occurred 3 hours after LPS injection when the number of CD11b+ cells was not changed. Whereas the expression of these pro-inflammatory genes had returned to basal by 48 hours when the highest number of CD11b+ cells in the brain was found, the expression of the anti-inflammatory cytokine IL-10 was still significantly up-regulated. This is important because the increased presence of CD11b+ cells in the CNS is often used as an indicator of neuroinflammation. While LPS did not affect the expression of the growth factors VEGF or BDNF, we observed that mechanical injury (caused by intraparenchymal injection) induced distinct patterns of microglial activation characterized by increased expression of VEGF and down-regulation of BDNF. It remains to be determined which type of microglia is more beneficial/detrimental to the CNS, but our data suggest that genetic traits determining microglial properties may have profound effect on many CNS pathologies.

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Section: Discussionsupporting

confidence: 51%

Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice

Nikodémová

Watters

2011

Neuroscience

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“…involved only a single acute exposure (10)(11)(12)(13)(14)(15). Few studies include multiple exposures to intact S. chartarum; we found four (16)(17)(18)(19).…”

mentioning

confidence: 70%

Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

Lichtenstein¹,

Molina²,

Donaghey³

et al. 2016

Am J Respir Cell Mol Biol

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After a single or multiple intratracheal instillations of Stachybotrys chartarum (S. chartarum or black mold) spores in BALB/c mice, we characterized cytokine production, metabolites, and inflammatory patterns by analyzing mouse bronchoalveolar lavage (BAL), lung tissue, and plasma. We found marked differences in BAL cell counts, especially large increases in lymphocytes and eosinophils in multipledosed mice. Formation of eosinophil-rich granulomas and airway goblet cell metaplasia were prevalent in the lungs of multiple-dosed mice but not in single-or saline-dosed groups. We detected changes in the cytokine expression profiles in both the BAL and plasma. Multiple pulmonary exposures to S. chartarum induced significant metabolic changes in the lungs but not in the plasma. These changes suggest a shift from type 1 inflammation after an acute exposure to type 2 inflammation after multiple exposures to S. chartarum. Eotaxin, vascular endothelial growth factor (VEGF), MIP-1a, MIP-1b, TNF-a, and the IL-8 analogs macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemoattractant (KC), had more dramatic changes in multiplethan in single-dosed mice, and parallel the cytokines that characterize humans with histories of mold exposures versus unexposed control subjects. This repeated exposure model allows us to more realistically characterize responses to mold, such as cytokine, metabolic, and cellular changes.

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“…There exists strong evidence that S . chartarum causes acute inflammatory responses, macrophage cytotoxicity [ 27 ], pulmonary hemorrhage [ 28 ], lung inflammation [ 29 , 30 ] and asthma-like responses [ 31 ] in mice. S .…”

Section: Introductionmentioning

confidence: 99%

Environmental Mold and Mycotoxin Exposures Elicit Specific Cytokine and Chemokine Responses

et al. 2015

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BackgroundMolds can cause respiratory symptoms and asthma. We sought to use isolated peripheral blood mononuclear cells (PBMCs) to understand changes in cytokine and chemokine levels in response to mold and mycotoxin exposures and to link these levels with respiratory symptoms in humans. We did this by utilizing an ex vivo assay approach to differentiate mold-exposed patients and unexposed controls. While circulating plasma chemokine and cytokine levels from these two groups might be similar, we hypothesized that by challenging their isolated white blood cells with mold or mold extracts, we would see a differential chemokine and cytokine release.Methods and FindingsPeripheral blood mononuclear cells (PBMCs) were isolated from blood from 33 patients with a history of mold exposures and from 17 controls. Cultured PBMCs were incubated with the most prominent Stachybotrys chartarum mycotoxin, satratoxin G, or with aqueous mold extract, ionomycin, or media, each with or without PMA. Additional PBMCs were exposed to spores of Aspergillus niger, Cladosporium herbarum and Penicillium chrysogenum. After 18 hours, cytokines and chemokines released into the culture medium were measured by multiplex assay. Clinical histories, physical examinations and pulmonary function tests were also conducted. After ex vivo PBMC exposures to molds or mycotoxins, the chemokine and cytokine profiles from patients with a history of mold exposure were significantly different from those of unexposed controls. In contrast, biomarker profiles from cells exposed to media alone showed no difference between the patients and controls.ConclusionsThese findings demonstrate that chronic mold exposures induced changes in inflammatory and immune system responses to specific mold and mycotoxin challenges. These responses can differentiate mold-exposed patients from unexposed controls. This strategy may be a powerful approach to document immune system responsiveness to molds and other inflammation-inducing environmental agents.

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Pulmonary Responses to Stachybotrys chartarum and Its Toxins: Mouse Strain Affects Clearance and Macrophage Cytotoxicity

Cited by 23 publications

References 54 publications

Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice

Outbred ICR/CD1 mice display more severe neuroinflammation mediated by microglial TLR4/CD14 activation than inbred C57Bl/6 mice

Repeated Mouse Lung Exposures toStachybotrys chartarumShift Immune Response from Type 1 to Type 2

Environmental Mold and Mycotoxin Exposures Elicit Specific Cytokine and Chemokine Responses

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