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

Morgan K Collins,Denay K Richards,Abigail M Shotland,Allison K Martin,Andrew P Fontenot,Shaikh M Atif,Morgan F Wade,Amy S Mckee,Manolo Torres-Llompart,Douglas G Mack

doi:10.1172/jci.insight.134356

Abstract

Chronic beryllium disease (CBD) is a metal hypersensitivity/autoimmune disease in which damage-associated molecular patterns (DAMPs) promote a break in T cell tolerance and expansion of Be2+/self-peptide-reactive CD4+ T cells. In this study, we investigated the mechanism of cell death induced by beryllium particles in alveolar macrophages (AMs) and its impact on DAMP release. We found that phagocytosis of Be led to AM cell death independent of caspase, receptor-interacting protein kinases 1 and 3, or ROS activity. Before cell death, Be-exposed AMs secreted TNF-α that boosted intracellular stores of IL-1α followed by caspase-8-dependent fragmentation of DNA. IL-1α and nucleosomal DNA were subsequently released from AMs upon loss of plasma membrane integrity. In contrast, necrotic AMs released only unfragmented DNA and necroptotic AMs released only IL-1α. In mice exposed to Be, TNF-α promoted release of DAMPs and was required for the mobilization of immunogenic DCs, the expansion of Be-reactive CD4+ T cells, and pulmonary inflammation in a mouse model of CBD. Thus, early autocrine effects of particle-induced TNF-α on AMs led to a break in peripheral tolerance. This potentially novel mechanism may underlie the known relationship between fine particle inhalation, TNF-α, and loss of peripheral tolerance in T cell-mediated autoimmune disease and hypersensitivities.

Highlights

Resident alveolar macrophages (AMs) exposed to a variety of particles can initiate inflammation via the release of damage-associated molecular patterns (DAMPs) [1, 2]
We have shown that AM cell death and DAMP release occur following single low-dose exposures to either beryllium sulfate or crystalline beryllium hydroxide (Be) particles [2]
DNA and IL-1α released from these cells act as DAMPs that promote recruitment of neutrophils and mobilization of immunogenic conventional dendritic cells (cDCs) [2, 12]

Summary

Introduction

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 regulate adaptive immune responses [1, 5, 7,8,9,10,11]. Exposure of AMs to crystalline forms of beryllium promotes their death and release of IL-1α and DNA These DAMPs drive accelerated migration of immunogenic cDCs from the lung to the lung-draining lymph nodes (LDLNs). While many types of particles can promote pulmonary disease via the activation of the innate immune system alone, others, such as beryllium, can promote development of T cell–mediated autoimmunity and hypersensitivity

Methods

Results

Conclusion