Inhaled Mine-Site Derived Metal Particulate Matter Drives Pulmonary and Systemic Immune Dysregulation

Project Summary/Abstract
Inhalation of mine site dust is a relevant route of human exposure to metal mixtures that poses a significant
health concern for tribal communities living near abandoned uranium and hard rock mine sites in the four-
corners region of the Southwestern United States. The University of New Mexico's Metals Exposure and
Toxicity Assessment on Tribal Land in the Southwest (UNM METALS) team has demonstrated that exposure
of individuals in the Navajo Nation to metal mixtures is associated with biomarkers of immune dysregulation
and living in close proximity to abandoned uranium mines correlates with levels of anti-nuclear autoantibodies.
This region is also a geographic epicenter for interstitial lung disease, silicosis and other chronic respiratory
disorders, which are linked to environmental exposures and systemic autoimmunity. It is currently not known
how inhaled metal-rich particulates drive extrapulmonary immunological dysregulation. In addition, the
contribution of different individual metals (e.g., uranium, vanadium, and iron) in driving these immune-mediated
changes has yet to be clearly defined. BioProject – Lung (BP Lung) focuses on investigating mechanisms of
metal-mediated immune dysregulation both locally in the lungs, as well as systemically following inhalation
exposure to metal-rich particulates. Thus, our main objective is to determine how these changes contribute to
pulmonary injury and autoimmune development. Because metals accumulate in bone and we have evidence
that inflammatory changes in the bone marrow niche mirror pulmonary responses following particulate
exposure, a second goal is to investigate crosstalk between the bone marrow niche and the lungs contributing
to metal particulate-mediated immune dysfunction. Our central hypothesis is that uranium and uranium-rich
particulate mixtures drive pulmonary and systemic immune dysregulation and autoimmunity through
hyperactive NETosis, in part by priming neutrophils for NETosis in the bone marrow niche. In Aim 1, we will
utilize a novel high content imaging, machine learning-based single cell platform to investigate how individual
metals alone or in combination with other metals and minerals contribute to oxidative stress, inflammation, and
NETosis using human, in vitro models. In Aim 2, we will use an autoimmune prone mouse model to determine
the role of neutrophils and NETosis in the development of airborne metal-mediated lung and systemic immune
dysregulation and autoimmune development using several established NETosis inhibitors. In Aim 3, we will
translate our mechanistic findings from Aims 1 and 2 to investigate associations between airborne metal
exposure and airway inflammatory mediators in individuals from Laguna Pueblo partnering community in
collaboration with BP Comm and CEC. This work is innovative and significant because it utilizes state-of-the
art tools to provide detailed understanding of the effect of neutrophils and NETosis as mechanistic targets and
driver of systemic immune dysregulation following metal particulate exposure and how crosstalk between the
bone marrow niche and the lungs contribute to these pathologies.

Grant Number: 4P42ES025589-09
NIH Institute/Center: NIH
Principal Investigator: Alicia Bolt