Silica-exposed mice generate autoantibodies to apoptotic cells

Pfau, Jean C.; Brown, Jared M.; Holian, Andrij

doi:10.1016/j.tox.2003.09.011

Cited by 81 publications

(62 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Regarding premorbid exposure to silica, only in mice (11,25) has there been a close examination of the relevant changes in systemic cytokine and lymphocyte marker profiles in this context. Recognizing that both immune activation and loss of peripheral tolerance to self are necessary for autoimmune phenomena, Pfau et al (25) have hypothesized that apoptosis exposes antigenic epitopes, otherwise nonexposed, that lead to reaction by the innate immune system.…”

Section: Discussionmentioning

confidence: 99%

“…Recognizing that both immune activation and loss of peripheral tolerance to self are necessary for autoimmune phenomena, Pfau et al (25) have hypothesized that apoptosis exposes antigenic epitopes, otherwise nonexposed, that lead to reaction by the innate immune system. Although our preliminary data appear to better support the earlier-described mechanism, i.e., an effect of altered autoimmunity due to changes in T regulatory cells, diverse mechanistic possibilities will need to be explored in more focused future studies.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cell markers, cytokines, and immune parameters in cement mason apprentices

Carlsten¹,

Roos²,

Kaufman³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. Cement masons are known to have significant silica exposure, and silica exposure and silicosis are thought to increase risk of autoimmune disease. Because the mechanisms remain obscure, with inconclusive reports of systemic immune effects following silica exposure, our goal was to identify potential early markers of silica-related immunologic and respiratory effects. Methods. We conducted a cross-sectional study of cement mason apprentices and electrician (control) apprentices. Demographics, dust exposure history, symptoms, spirometry, exhaled nitric oxide, and blood (for immunoglobulins, cytokines, cell counts, and surface markers) were obtained from 11 cement mason apprentices and a comparison group of 21 electrician apprentices. Results. Masons had significantly higher (P < 0.05) masonry dust exposure (42 versus 9 dust-hour-years), serum interleukin-1␤ (IL-1␤; 12 versus 9 pg/ml), IL-2 (20 versus 8 pg/ml), IL-4 (193 versus 67 pg/ml), IL-10 (44 versus 21 pg/ml), and interferon-␥ (139 versus 65 pg/ml) compared with electricians. In contrast, masons had significantly lower percentages of CD25؉ (12% versus 20%) and CD69؉ (4% versus 9%) lymphocytes. Conclusion. Mason apprentices had higher levels of serum proinflammatory cytokines and lower percentages of CD25؉ and CD69؉ lymphocytes than did electrician apprentices. These preliminary findings suggest that mason apprentices may be at greater risk of a systemic proinflammatory state that is potentially linked to immune dysregulation. Although distinct limitations of this preliminary data are recognized, this is consistent with early biologic effects leading to increased incidence of autoimmune disease among silica-exposed workers. Prospective studies are needed to validate these initial findings and clarify the temporal sequence of observed relationships.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cell markers, cytokines, and immune parameters in cement mason apprentices

Carlsten¹,

Roos²,

Kaufman³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…This model was further used to show that silica-exposed mice generated autoantibodies to apoptotic cells. By inducing apoptosis in MH-S murine macrophages and staining with serum from NZM mice, they were able to establish that only apoptotic cells or lysates from apoptotic cells reacted to serum containing autoantibodies, unlike necrotic cell or live cells [115]. Finally, the same group successfully reversed the silicainduced exacerbation of autoimmune disease in the NZM mice by using weekly instillations of rottlerin (apoptosis inhibitor disrupting PKCδ pathway) confirming the hypothesis that silica-induced AM apoptosis was probably responsible for auto-antigen production leading to enhanced autoimmune disease [116].…”

Section: The Role Of Silica Exposure In Macrophage Immune Dysfunctionmentioning

confidence: 99%

Silica binding and toxicity in alveolar macrophages

Hamilton

Thakur

Holian

2008

Free Radical Biology and Medicine

Self Cite

326

234

View full text Add to dashboard Cite

Inhalation of the crystalline form of silica is associated with a variety of pathologies from acute lung inflammation to silicosis, in addition to autoimmune disorders and cancer. Basic science researchers looking at the mechanisms involved with the earliest initiators of disease are focused on how the alveolar macrophage (AM) interacts with the inhaled silica particle and the consequences of silicainduced toxicity on the cellular level. Based on experimental results, several rationales have been developed on exactly how crystalline silica particles are toxic to the macrophage cell that is functionally responsible for clearance of the foreign particle. For example, silica is capable of producing reactive oxygen species (ROS) either directly (on the particle surface) or indirectly (produced by the cell as a response to silica) triggering cell-signaling pathways initiating cytokine release and apoptosis. With murine macrophages, reactive nitrogen species (RNS) are produced in the initial respiratory burst in addition to ROS. An alternative explanation for silica toxicity includes lysosomal permeability, where silica disrupts the normal internalization process leading to cytokine release and cell death. Still other research has focused on the cell surface receptors (collectively known as scavenger receptors) involved in silica binding and internalization. The silica-induced cytokine release and apoptosis is described as the function of receptor-mediated signaling rather than free radical damage. Current research ideas on silica toxicity and binding in the alveolar macrophage are reviewed and discussed.

show abstract

“…Silica has been reported to induce apoptosis of alveolar macrophages and a dysregulation of apoptosis due to silica exposure has been implicated in disease processes including inflammation, fibrosis and autoimmunity (8,(25)(26)(27)(28)(29)(30). For example, in vivo treatment of silica-exposed mice with caspase inhibitors has been reported to significantly inhibit neutrophil accumulation and alleviate pulmonary inflammation (27).…”

Section: W-shmentioning

confidence: 99%

Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

Brown

Swindle

Kushnir-Sukhov

et al. 2007

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Inhalation of crystalline silica results in pulmonary fibrosis and silicosis. It has been suggested that mast cells play a role in these conditions. How mast cells would influence pathology is unknown. We thus explored mast cell interactions with silica in vitro and in B6.CgKit W-sh mast cell-deficient mice. B6.Cg-Kit W-sh mice did not develop inflammation or significant collagen deposition after instillation of silica, while C57Bl/6 wild-type mice did have these findings. Given this supporting evidence of a role for mast cells in the development of silicosis, we examined the ability of silica to activate mouse bone marrow-derived mast cells (BMMC), including degranulation (␤-hexosaminidase release); production of reactive oxygen species (ROS) and inflammatory mediators; and the effects of silica on Fc⑀RI-dependent activation. Silica did not induce mast cell degranulation. However, TNF-␣, IL-13, monocyte chemotactic protein-1, protease activity, and production of ROS were dose-dependently increased after silica exposure, and production was enhanced after Fc⑀RI stimulation. This mast cell activation was inhibited by anti-inflammatory compounds. As silica mediates some effects in macrophages through scavenger receptors (SRs), we first determined that mast cells express scavenger receptors; then explored the involvement of SR-A and macrophage receptor with colleagenous structure (MARCO). Silica-induced ROS formation, apoptosis, and TNF-␣ production were reduced in BMMC obtained from SR-A, MARCO, and SR-A/MARCO knockout mice. These findings demonstrate that silica directs mast cell production of inflammatory mediators, in part through SRs, providing insight into critical events in the pathogenesis and potential therapeutic targets in silicosis. Keywords: B6.Cg-kitW-sh sash mouse; CD204; macrophage receptor with collagenous structure; mast cell; silicosis; SR-A Among environmental exposures that lead to pathologic changes in tissues is crystalline silica, which can result in occupational silicosis from inhalation of silica dusts in manufacturing, construction, farming, and mining operations. Silicosis, for which there is no effective treatment, leads to decreased pulmonary function and increased susceptibility to diseases of the respiratory tract (1, 2).Involvement of mast cells in silica-induced pulmonary inflammation has been suggested by two clinical observations. First, the number of mast cells within the lungs of individuals exposed to silica dust is increased (3). Second, an increase in mast cells staining for basic fibroblast growth factor located within silicotic nodules has been reported in lung sections obtained from patients with silicosis (4). Despite the suggestive CLINICAL RELEVANCEThis study demonstrates a role for mast cells in silicosis and is the first study to examine direct effects of silica on mast cell biology. It provides evidence that treatment of silicosis should explore mast cells as a potential therapeutic target.evidence for a role of mast cells in the development of silicosis, there are ...

show abstract

Silica-exposed mice generate autoantibodies to apoptotic cells

Cited by 81 publications

References 20 publications

Cell markers, cytokines, and immune parameters in cement mason apprentices

Cell markers, cytokines, and immune parameters in cement mason apprentices

Silica binding and toxicity in alveolar macrophages

Silica-Directed Mast Cell Activation Is Enhanced by Scavenger Receptors

Contact Info

Product

Resources

About