Lung Inflammatory Response to Environmental Dust Exposure in Mice Suggests a Link to Regional Respiratory Disease Risk.

PURPOSE: The Salton Sea, California's largest lake, is designated as an agricultural drainage reservoir. In recent years, the lake has experienced shrinkage due to reduced water sources, increasing levels of aerosolized dusts in surrounding regions. Communities surrounding the Salton Sea have increased asthma prevalence versus the rest of California; however, a connection between dust inhalation and lung health impacts has not been defined. METHODS: We used an established intranasal dust exposure murine model to study the lung inflammatory response following single or repetitive (7-day) exposure to extracts of dusts collected in regions surrounding the Salton Sea (SSDE), complemented with in vitro investigations assessing SSDE impacts on the airway epithelium. RESULTS: In these investigations, single or repetitive SSDE exposure induced significant lung inflammatory cytokine release concomitant with neutrophil influx. Repetitive SSDE exposure led to significant lung eosinophil recruitment and altered expression of genes associated with allergen-mediated immune response, including Clec4e. SSDE treatment of human bronchial epithelial cells (BEAS-2B) induced inflammatory cytokine production at 5- and 24-hours post-treatment. When BEAS-2B were exposed to protease activity-depleted SSDE (PDSSDE) or treated with SSDE in the context of protease-activated receptor-1 and -2 antagonism, inflammatory cytokine release was decreased. Furthermore, repetitive exposure to PDSSDE led to decreased neutrophil and eosinophilic influx and IL-6 release in mice compared to SSDE-challenged mice. CONCLUSION: These investigations demonstrate potent lung inflammatory responses and tissue remodeling in response to SSDE, in part due to environmental proteases found within the dusts. These studies provide the first evidence supporting a link between environmental dust exposure, protease-mediated immune activation, and respiratory disease in the Salton Sea region.

Hematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages.

Resistin-like molecule α (RELMα) is a highly secreted protein in type 2 (Th2) cytokine-induced inflammation including helminth infection and allergy. In infection with Nippostrongylus brasiliensis (Nb), RELMα dampens Th2 inflammatory responses. RELMα is expressed by immune cells, and by epithelial cells (EC); however, the functional impact of immune versus EC-derived RELMα is unknown. We generated bone marrow (BM) chimeras that were RELMα deficient (RELMα-/- ) in BM or non BM cells and infected them with Nb. Non BM RELMα-/- chimeras had comparable inflammatory responses and parasite burdens to RELMα+/+ mice. In contrast, both RELMα-/- and BM RELMα-/- mice exhibited increased Nb-induced lung and intestinal inflammation, correlated with elevated Th2 cytokines and Nb killing. CD11c+ lung macrophages were the dominant BM-derived source of RELMα and can mediate Nb killing. Therefore, we employed a macrophage-worm co-culture system to investigate whether RELMα regulates macrophage-mediated Nb killing. Compared to RELMα+/+ macrophages, RELMα-/- macrophages exhibited increased binding to Nb and functionally impaired Nb development. Supplementation with recombinant RELMα partially reversed this phenotype. Gene expression analysis revealed that RELMα decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage-mediated helminth killing. Collectively, these studies demonstrate that BM-derived RELMα is necessary and sufficient to dampen Nb immune responses, and identify that one mechanism of action of RELMα is through inhibiting macrophage recruitment and interaction with Nb. Our findings suggest that RELMα acts as an immune brake that provides mutually beneficial effects for the host and parasite by limiting tissue damage and delaying parasite expulsion.

Continuous Inhalation Exposure to Fungal Allergen Particulates Induces Lung Inflammation While Reducing Innate Immune Molecule Expression in the Brainstem.

Continuous exposure to aerosolized fine (particle size ≤2.5 µm) and ultrafine (particle size ≤0.1 µm) particulates can trigger innate inflammatory responses in the lung and brain depending on particle composition. Most studies of manmade toxicants use inhalation exposure routes, whereas most studies of allergens use soluble solutions administered via intranasal or injection routes. Here, we tested whether continuous inhalation exposure to aerosolized Alternaria alternata particulates (a common fungal allergen associated with asthma) would induce innate inflammatory responses in the lung and brain. By designing a new environmental chamber able to control particle size distribution and mass concentration, we continuously exposed adult mice to aerosolized ultrafine Alternaria particulates for 96 hr. Despite induction of innate immune responses in the lung, induction of innate immune responses in whole brain samples was not detected by quantitative polymerase chain reaction or flow cytometry. However, exposure did trigger decreases in Arginase 1, inducible nitric oxide synthase, and tumor necrosis factor alpha mRNA in the brainstem samples containing the central nervous system respiratory circuit (the dorsal respiratory group, ventral respiratory group, and the pre-Bötzinger and Bötzinger complexes). In addition, a significant decrease in the percentage of Toll-like receptor 2-expressing brainstem microglia was detected by flow cytometry. Histologic analysis revealed a significant decrease in Iba1 but not glial fibrillary acidic protein immunoreactivity in both the brainstem and the hippocampus. Together these data indicate that inhalation exposure to a natural fungal allergen under conditions sufficient to induce lung inflammation surprisingly causes reductions in baseline expression of select innate immune molecules (similar to that observed during endotoxin tolerance) in the region of the central nervous system controlling respiration.