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Am J Transl Res 2013;5(2):224-234
Original Article
Exposure to fine airborne particulate matter induces macrophage
infiltration, unfolded protein response, and lipid deposition in white
adipose tissue
Roberto Mendez, Ze Zheng, Zhongjie Fan, Sanjay Rajagopalan, Qinghua Sun, Kezhong Zhang
Center for Molecular Medicine and Genetics, Department of Immunology and Microbiology, Wayne State University
School of Medicine, De-troit, MI 48201, USA; Division of Cardiovascular Medicine, Davis Heart and Lung Research
Institute, College of Medicine, Division of Environmental Health Sciences, College of Public Health, Ohio State
University, Columbus, OH 43210, USA; Department of Cardiology, Peking Union Medical College Hospital,
Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Received December 17, 2012; Accepted February 15, 2013; Epub March 28, 2013; Published April 8, 2013
Abstract: Recent epidemiological studies have suggested a link between exposure to ambient air-pollution and
susceptibility to metabolic disorders such as Type II diabetes mellitus. Previously, we provided evidence that both
short- and long-term exposure to concentrated ambient particulate matter with aerodynamic diameter <2.5 µm
(PM2.5) induces multiple abnormalities associated with the pathogenesis of Type II diabetes mellitus, including
insulin resistance, visceral adipose inflammation, brown adipose mitochondrial adipose changes, and hepatic
endoplasmic reticulum (ER) stress. In this report, we show that chronic inhalation exposure to PM2.5 (10 months
exposure) induces macrophage infiltration and Unfolded Protein Response (UPR), an intracellular stress
signaling that regulates cell metabolism and survival, in mouse white adipose tissue in vivo. Gene expression
studies suggested that PM2.5 exposure induces two distinct UPR signaling pathways mediated through the UPR
transducer inositol-requiring 1α (IRE1α): 1) ER-associated Degradation (ERAD) of unfolded or misfolded
proteins, and 2) Regulated IRE1-dependent Decay (RIDD) of mRNAs. Along with the induction of the UPR
pathways and macrophage infiltration, expression of genes involved in lipogenesis, adipocyte differentiation, and
lipid droplet formation was increased in the adipose tissue of the mice exposed to PM2.5. In vitro study confirmed
that PM2.5 can trigger phosphorylation of the UPR transducer IRE1α and activation of macrophages. These
results provide novel insights into PM2.5-triggered cell stress response in adipose tissue and increase our
understanding of pathophysiological effects of particulate air pollution on the development of metabolic disorders
(AJTR1212005).
Keywords: Ambient particulate matter, PM2.5, unfolded protein response, lipid metabolism, white adipose tissue
Address correspondence to: Dr. Kezhong Zhang, Center for Molecular Medicine and Genetics, Wayne State
University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, USA. Phone: 313-577-2669; Fax: 313-
577-5218; E-mail: kzhang@med.wayne.edu; Dr. Qinghua Sun, Division of Environmental Health Sciences,
College of Public Health, Ohio State University, Columbus, OH 43210, USA. Phone: 614-247-1560; Fax: 614-688-
4233; E-mail: sun.224@osu.edu
Original Article
Exposure to fine airborne particulate matter induces macrophage
infiltration, unfolded protein response, and lipid deposition in white
adipose tissue
Roberto Mendez, Ze Zheng, Zhongjie Fan, Sanjay Rajagopalan, Qinghua Sun, Kezhong Zhang
Center for Molecular Medicine and Genetics, Department of Immunology and Microbiology, Wayne State University
School of Medicine, De-troit, MI 48201, USA; Division of Cardiovascular Medicine, Davis Heart and Lung Research
Institute, College of Medicine, Division of Environmental Health Sciences, College of Public Health, Ohio State
University, Columbus, OH 43210, USA; Department of Cardiology, Peking Union Medical College Hospital,
Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
Received December 17, 2012; Accepted February 15, 2013; Epub March 28, 2013; Published April 8, 2013
Abstract: Recent epidemiological studies have suggested a link between exposure to ambient air-pollution and
susceptibility to metabolic disorders such as Type II diabetes mellitus. Previously, we provided evidence that both
short- and long-term exposure to concentrated ambient particulate matter with aerodynamic diameter <2.5 µm
(PM2.5) induces multiple abnormalities associated with the pathogenesis of Type II diabetes mellitus, including
insulin resistance, visceral adipose inflammation, brown adipose mitochondrial adipose changes, and hepatic
endoplasmic reticulum (ER) stress. In this report, we show that chronic inhalation exposure to PM2.5 (10 months
exposure) induces macrophage infiltration and Unfolded Protein Response (UPR), an intracellular stress
signaling that regulates cell metabolism and survival, in mouse white adipose tissue in vivo. Gene expression
studies suggested that PM2.5 exposure induces two distinct UPR signaling pathways mediated through the UPR
transducer inositol-requiring 1α (IRE1α): 1) ER-associated Degradation (ERAD) of unfolded or misfolded
proteins, and 2) Regulated IRE1-dependent Decay (RIDD) of mRNAs. Along with the induction of the UPR
pathways and macrophage infiltration, expression of genes involved in lipogenesis, adipocyte differentiation, and
lipid droplet formation was increased in the adipose tissue of the mice exposed to PM2.5. In vitro study confirmed
that PM2.5 can trigger phosphorylation of the UPR transducer IRE1α and activation of macrophages. These
results provide novel insights into PM2.5-triggered cell stress response in adipose tissue and increase our
understanding of pathophysiological effects of particulate air pollution on the development of metabolic disorders
(AJTR1212005).
Keywords: Ambient particulate matter, PM2.5, unfolded protein response, lipid metabolism, white adipose tissue
Address correspondence to: Dr. Kezhong Zhang, Center for Molecular Medicine and Genetics, Wayne State
University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, USA. Phone: 313-577-2669; Fax: 313-
577-5218; E-mail: kzhang@med.wayne.edu; Dr. Qinghua Sun, Division of Environmental Health Sciences,
College of Public Health, Ohio State University, Columbus, OH 43210, USA. Phone: 614-247-1560; Fax: 614-688-
4233; E-mail: sun.224@osu.edu
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