Synergistic Effect of WTC-Particulate Matter and Lysophosphatidic Acid Exposure and the Role of RAGE: In-Vitro and Translational Assessment

Abstract

World Trade Center particulate matter (WTC-PM)-exposed firefighters with metabolic syndrome (MetSyn) have a higher risk of WTC lung injury (WTC-LI). Since macrophages are crucial innate pulmonary mediators, we investigated WTC-PM/lysophosphatidic acid (LPA) co-exposure in macrophages. LPA, a low-density lipoprotein metabolite, is a ligand of the advanced glycation end-products receptor (AGER or RAGE). LPA and RAGE are biomarkers of WTC-LI. Human and murine macrophages were exposed to WTC-PM, and/or LPA, and compared to controls. Supernatants were assessed for cytokines/chemokines; cell lysate immunoblots were assessed for signaling intermediates after 24 h. To explore the translatability of our in-vitro findings, we assessed serum cytokines/chemokines and metabolites of symptomatic, never-smoking WTC-exposed firefighters. Agglomerative hierarchical clustering identified phenotypes of WTC-PM-induced inflammation. WTC-PM induced GM-CSF, IL-8, IL-10, and MCP-1 in THP-1-derived macrophages and induced IL-1α, IL-10, TNF-α, and NF-κB in RAW264.7 murine macrophage-like cells. Co-exposure induced synergistic elaboration of IL-10 and MCP-1 in THP-1-derived macrophages. Similarly, co-exposure synergistically induced IL-10 in murine macrophages. Synergistic effects were seen in the context of a downregulation of NF-κB, p-Akt, -STAT3, and -STAT5b. RAGE expression after co-exposure increased in murine macrophages compared to controls. In our integrated analysis, the human cytokine/chemokine biomarker profile of WTC-LI was associated with discriminatory metabolites (fatty acids, sphingolipids, and amino acids). LPA synergistically elaborated WTC-PM’s inflammatory effects in vitro and was partly RAGE-mediated. Further research will focus on the intersection of MetSyn/PM exposure.

Molecular Clustering Analysis of Blood Biomarkers in World Trade Center Exposed Community Members with Persistent Lower Respiratory Symptoms

“…WTCS cluster 2 was characterized by circulating inflammatory and remodeling markers including MMP1, 2, 3, 8, 12, 13, soluble receptors RAGE, IL-1RA, IL-6Ra, TNFRI, TNFRII, and chemokines IL-8, and CCL17. Many of these biomarkers, in particular MMP's and RAGE, have previously been reported to be very important to understand the responses in the WTC responders, signifying either a prediction of protection or worsening of lung function [18,[23][24][25][26]57]. Our data cannot predict lung function measured by spirometry because participants were enrolled based on normal spirometry measurements ( [5], Table 1).…”

Dietary Phenotype and Advanced Glycation End-Products Predict WTC-Obstructive Airways Disease: a Longitudinal Observational Study

“…Cases of WTC-OAD had either WTC-Lung Injury (WTC-LI; FEV 1 <LLN) and/or Airway Hyperresponsiveness (AHR;positive methacholine or positive bronchodilator testing) at any time point post-9/11 (N=921). (22)(23)(24)(25)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67) Cases of WTC-OAD were compared to N=3,094 without WTC-OAD at any time after 9/11.…”

Glycation and a Spark of ALEs (Advanced Lipoxidation End Products) – Igniting RAGE/Diaphanous-1 and Cardiometabolic Disease

“…It is noteworthy that distinct studies implicated LPA-RAGE interaction in lung, mammary and ovarian tumors (14, 15). Other studies suggested roles for LPA-RAGE in stroke (16) and upon exposure to World Trade Center particulate matter, the released LPA induced inflammation in macrophages, at least in part through RAGE (17).…”