Brucella abortus Induces the Secretion of Proinflammatory Mediators from Glial Cells Leading to Astrocyte Apoptosis

Samartino, Clara García; Delpino, M. Victoria; Godoy, Clara Pott; Genaro, María Silvia Di; Pasquevich, Karina A.; Zwerdling, Astrid; Barrionuevo, Paula; Mathieu, Patricia; Cassataro, Juliana; Pitossi, Fernando Juan; Giambartolomei, Guillermo H.

doi:10.2353/ajpath.2010.090503

Cited by 65 publications

(107 citation statements)

References 60 publications

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“…are mainly adapted to establish chronic infections in macrophages (3). Thus, our results suggest that osteoblasts do not constitute a survival niche for long-term Brucella persistence in osteoarticular localization and go along with the fact that B. abortus can induce apoptosis of cell types other than macrophages (13,15). We hypothesize that apart from resident macrophages, other monocytes/macrophages could be attracted to the site of osteoarticular infection through MCP-1 secretion mediated by B. abortus-infected osteoblasts, increasing the likelihood of finding a replicative niche.…”

Section: Discussionmentioning

confidence: 87%

Section: B Abortus Invades and Multiplies In Primary Mouse Osteoblasmentioning

confidence: 99%

“…abortus-mediated apoptosis has been reported for a variety of cells, including astrocytes and hepatocytes (13,15). In particular, it has been demonstrated that astrocyte apoptosis induced by B. abortus infection involves caspase activation (15). To determine the role of caspases in osteoblast apoptosis induced by B. abortus, these cells were treated with a general caspase inhibitor (Z-VAD-FMK) and then infected with B. abortus at an MOI of 100.…”

Section: B Abortus Invades and Multiplies In Primary Mouse Osteoblasmentioning

confidence: 99%

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Brucella abortus Invasion of Osteoblasts Inhibits Bone Formation

et al. 2012

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ABSTRACTOsteoarticular brucellosis is the most common presentation of the active disease in humans. Loss of bone is a serious complication of localized bacterial infection of bones or the adjacent tissue, and brucellosis proved not to be the exception. The skeleton is a dynamic organ system which is constantly remodeled. Osteoblasts are responsible for the deposition of bone matrix and are thought to facilitate the calcification and mineralization of the bone matrix, and their function could be altered under infectious conditions. In this article, we describe immune mechanisms wherebyBrucella abortusmay invade and replicate within osteoblasts, inducing apoptosis, inhibiting mineral and organic matrix deposition, and inducing upregulation of RANKL expression. Additionally, all of these mechanisms contributed in different ways to bone loss. These processes implicate the activation of signaling pathways (mitogen-activated protein kinases [MAPK] and caspases) involved in cytokine secretion, expression of activating molecules, and cell death of osteoblasts. In addition, considering the relevance of macrophages in intracellularBrucellasurvival and proinflammatory cytokine secretion in response to infection, we also investigated the role of these cells as modulators of osteoblast survival, differentiation, and function. We demonstrated that supernatants fromB. abortus-infected macrophages may also mediate osteoblast apoptosis and inhibit osteoblast function in a process that is dependent on the presence of tumor necrosis factor alpha (TNF-α). These results indicate thatB. abortusmay directly and indirectly harm osteoblast function, contributing to the bone and joint destruction observed in patients with osteoarticular complications of brucellosis.

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Section: Discussionmentioning

confidence: 87%

Section: B Abortus Invades and Multiplies In Primary Mouse Osteoblasmentioning

confidence: 99%

Section: B Abortus Invades and Multiplies In Primary Mouse Osteoblasmentioning

confidence: 99%

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Brucella abortus Invasion of Osteoblasts Inhibits Bone Formation

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“…In line with this last property we found that heat-killed B. abortus (HKBA) can stimulate cytokine and MMP-2 production by human FLS, clearly indicating that these FLS responses may be elicited by one or more structural components of B. abortus. Since Brucella lipoproteins induce the production of proinflammatory cytokines in several cell types (13,14,59) and can also induce MMP-9 production by human monocytes (41), we hypothesized that such lipoproteins could also stimulate the production of cytokines and MMP-2 in FLS. Using Omp19 as a model Brucella lipoprotein, we found that its lipidated version (L-Omp19), but not its unlipidated form, induced the production of proinflammatory cytokines and MMP-2 by FLS.…”

Section: Discussionmentioning

confidence: 99%

“…7, FLS stimulated with HKBA produced elevated levels of GM-CSF, IL-6, IL-8, and MCP-1, in general in a dose-dependent fashion, indicating that the secretion of these factors can be stimulated by a structural component of B. abortus. Since we previously found that B. abortus lipoproteins induce cytokine, chemokine, and MMP secretion in different cell types (13,14,41,59), we hypothesized that lipoproteins could also mediate such effects in FLS.…”

Section: Brucella Abortus-induced Secretion Of Mmp-2 and Cytokines Inmentioning

confidence: 99%

Potential Role of Fibroblast-Like Synoviocytes in Joint Damage Induced by Brucella abortus Infection through Production and Induction of Matrix Metalloproteinases

et al. 2011

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Brucella abortus‐activated microglia induce neuronal death through primary phagocytosis

Rodrı́guez

Delpino

Miraglia

et al. 2017

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Inflammation has long been implicated as a contributor to pathogenesis in neurobrucellosis. Many of the associated neurocognitive symptoms of neurobrucellosis may be the result of neuronal dysfunction resulting from the inflammatory response induced by Brucella abortus infection in the central nervous system. In this manuscript, we describe an immune mechanism for inflammatory activation of microglia that leads to neuronal death upon B. abortus infection. B. abortus was unable to infect or harm primary cultures of mouse neurons. However, when neurons were co-cultured with microglia and infected with B. abortus significant neuronal loss occurred. This phenomenon was dependent on TLR2 activation by Brucella lipoproteins. Neuronal death was not due to apoptosis, but it was dependent on the microglial release of nitric oxide (NO). B. abortus infection stimulated microglial proliferation, phagocytic activity and engulfment of neurons. NO secreted by B. abortus-activated microglia induced neuronal exposure of the "eat-me" signal phosphatidylserine (PS). Blocking of PS-binding to protein milk fat globule epidermal growth factor-8 (MFG-E8) or microglial vitronectin receptor-MFG-E8 interaction was sufficient to prevent neuronal loss by inhibiting microglial phagocytosis without affecting their activation. Taken together, our results indicate that B. abortus is not directly toxic to neurons; rather, these cells become distressed and are killed by phagocytosis in the inflammatory surroundings generated by infected microglia. Neuronal loss induced by B. abortus-activated microglia may explain, in part, the neurological deficits observed during neurobrucellosis.

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Brucella abortus Induces the Secretion of Proinflammatory Mediators from Glial Cells Leading to Astrocyte Apoptosis

Abstract: Central nervous system (CNS) invasion by bacteria of the genus

Cited by 65 publications

References 60 publications

Brucella abortus Invasion of Osteoblasts Inhibits Bone Formation

Brucella abortus Invasion of Osteoblasts Inhibits Bone Formation

Potential Role of Fibroblast-Like Synoviocytes in Joint Damage Induced by Brucella abortus Infection through Production and Induction of Matrix Metalloproteinases

Brucella abortus‐activated microglia induce neuronal death through primary phagocytosis

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