TY - JOUR
T1 - Synergistic effect of WTC-particulate matter and lysophosphatidic acid exposure and the role of RAGE
T2 - In-vitro and translational assessment
AU - Lam, Rachel
AU - Haider, Syed H.
AU - Crowley, George
AU - Caraher, Erin J.
AU - Ostrofsky, Dean F.
AU - Talusan, Angela
AU - Kwon, Sophia
AU - Prezant, David J.
AU - Wang, Yuyan
AU - Liu, Mengling
AU - Nolan, Anna
N1 - Funding Information:
NHLBI R01HL119326 and CDC/NIOSH U01-OH011300. Clinical Center of Excellence 200-2017-93426, Data Center 200-2017-93326. This work was partially funded by the NYU-HHC CTSI, supported by grant UL1TR000038 via the Saperstein Scholars Fund. The funding agencies did not participate in the study design; in collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the article for publication. This work is dedicated to the FDNY rescue workers, and we would like to thank them for their bravery, sacrifice, and continued commitment to our work.
Funding Information:
Funding: NHLBI R01HL119326 and CDC/NIOSH U01-OH011300. Clinical Center of Excellence 200-2017-93426, Data Center 200-2017-93326. This work was partially funded by the NYU-HHC CTSI, supported by grant UL1TR000038 via the Saperstein Scholars Fund. The funding agencies did not participate in the study design; in collection, analysis or interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/6/2
Y1 - 2020/6/2
N2 - 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.
AB - 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.
KW - Lysophosphatidic acid
KW - Particulate matter exposure
KW - RAGE
KW - Synergy
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U2 - 10.3390/ijerph17124318
DO - 10.3390/ijerph17124318
M3 - Article
C2 - 32560330
AN - SCOPUS:85086753360
VL - 17
SP - 1
EP - 22
JO - International Journal of Environmental Research and Public Health
JF - International Journal of Environmental Research and Public Health
SN - 1661-7827
IS - 12
M1 - 4318
ER -