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 CD80 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 CD80 DCs in the LDLNs, whereas blocking both pathways prevented accumulation of CD80 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.

A role for TNF-α in alveolar macrophage damage-associated molecular pattern release

“…Resident alveolar macrophages (AMs) exposed to a variety of particles can initiate inflammation via the release of damage-associated molecular patterns (DAMPs) (1,2). Sterile particles with crystalline morphology (e.g., metal hydroxide salts, silica) promote cell stress and in some cases cell death in macrophages (1)(2)(3)(4)(5)(6).…”

“…Resident alveolar macrophages (AMs) exposed to a variety of particles can initiate inflammation via the release of damage-associated molecular patterns (DAMPs) (1,2). Sterile particles with crystalline morphology (e.g., metal hydroxide salts, silica) promote cell stress and in some cases cell death in macrophages (1)(2)(3)(4)(5)(6). These factors drive lung inflammation and promote upregulation of costimulatory molecules on pulmonary conventional dendritic cells (cDCs) and thus regulate adaptive immune responses (1,5,(7)(8)(9)(10)(11).…”

“…Here, they can present a subset of self-peptides on Be 2+ -modified HLA-DP2 molecules to naive CD4 + T cells in a manner that breaks peripheral tolerance (2,12,24,25). Once activated, Be 2+ /HLA-DP2-presented self-peptide-reactive (Be 2+ /self-peptide-reactive) CD4 + T cells differentiate into IFN-γ-secreting CD4 + effector T (T eff ) cells that are licensed to enter the lung tissue (2,12,(26)(27)(28). There, they respond to Be 2+ /self-peptides presented by antigen-presenting cells and orchestrate chronic pulmonary inflammation and progressive fibrosis.…”

“…The high expression of these molecules on immunogenic cDCs provides survival signals to naive T cells responding to the presented antigen (32)(33)(34)(35). We have shown that AM cell death and DAMP release occur following single low-dose exposures to either beryllium sulfate (which forms beryllium hydroxide in airway fluids) or crystalline beryllium hydroxide (Be) particles (2). DNA and IL-1α released from Be-exposed AMs induce upregulation of CD80 on cDCs via the MyD88-dependent receptors TLR9 and IL-1R1 (2,12,36).…”

“…We have shown that AM cell death and DAMP release occur following single low-dose exposures to either beryllium sulfate (which forms beryllium hydroxide in airway fluids) or crystalline beryllium hydroxide (Be) particles (2). DNA and IL-1α released from Be-exposed AMs induce upregulation of CD80 on cDCs via the MyD88-dependent receptors TLR9 and IL-1R1 (2,12,36). In addition, DNA released by Be-exposed AMs promotes accelerated migration of cDCs from the lung to the LDLNs via TLR9 (2).…”