TLR9 and IL-1R1 Promote Mobilization of Pulmonary Dendritic Cells during Beryllium Sensitization.

Abstract

Metal-induced hypersensitivity is driven by dendritic cells (DCs) that migrate from the site of exposure to the lymph nodes, upregulate costimulatory molecules, and initiate metal-specific CD4+ T cell responses. Chronic beryllium disease (CBD), a life-threatening metal-induced hypersensitivity, is driven by beryllium-specific CD4+ Th1 cells that expand in the lung-draining lymph nodes (LDLNs) after beryllium exposure (sensitization phase) and are recruited back to the lung, where they orchestrate granulomatous lung disease (elicitation phase). To understand more about how beryllium exposures impact DC function during sensitization, we examined the early events in the lung and LDLNs after pulmonary exposure to different physiochemical forms of beryllium. Exposure to soluble or crystalline forms of beryllium induced alveolar macrophage death/release of IL-1α and DNA, enhanced migration of CD80hi DCs to the LDLNs, and sensitized HLA-DP2 transgenic mice after single low-dose exposures, whereas exposures to insoluble particulate forms beryllium did not. IL-1α and DNA released by alveolar macrophages upregulated CD80 on immature BMDC via IL-1R1 and TLR9, respectively. Intrapulmonary exposure of mice to IL-1R and TLR9 agonists without beryllium was sufficient to drive accumulation of CD80hi DCs in the LDLNs, whereas blocking both pathways prevented accumulation of CD80hi DCs in the LDLNs of beryllium-exposed mice. Thus, in contrast to particulate forms of beryllium, which are poor sensitizers, soluble or crystalline forms of beryllium promote death of alveolar macrophages and their release of IL-1α and DNA, which act as damage-associated molecular pattern molecules to enhance DC function during beryllium sensitization.

• Authors: Morgan F Wade, Morgan K Collins, Denay Richards, Douglas G Mack, Allison K Martin, Charles A Dinarello, Andrew P Fontenot, Amy S McKee
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 201 Issue 8 Pg. 2232-2243 (10 15 2018) ISSN: 1550-6606 [Electronic] United States
• PMID: 30185516 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2018 by The American Association of Immunologists, Inc.

Chemical References

• Allergens
• IL1R1 protein, mouse
• Myeloid Differentiation Factor 88
• Receptors, Interleukin-1 Type I
• Toll-Like Receptor 9
• Beryllium

Topics

• Allergens (immunology)
• Animals
• Berylliosis (immunology)
• Beryllium (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Cell Differentiation
• Cell Movement
• Cells, Cultured
• Chronic Disease
• Dendritic Cells (immunology)
• Enzyme-Linked Immunospot Assay
• Humans
• Hypersensitivity (immunology)
• Immunization
• Lung (pathology)
• Lymphocyte Activation
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics)
• Receptors, Interleukin-1 Type I (metabolism)
• Toll-Like Receptor 9 (metabolism)