Induction of ER stress in macrophages of tuberculosis granulomas

Seimon, Tracie A., Kim, Mi-Jeong, Blumenthal, Antje, Koo, Jovanka, Ehrt, Sabine, Wainwright, Helen, Bekker, Linda-Gail, Kaplan, Gilla, Nathan, Carl, Tabas, Ira and Russell, David G. (2010) Induction of ER stress in macrophages of tuberculosis granulomas. PLoS One, 5 9: e12772.1-e12772.12. doi:10.1371/journal.pone.0012772

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Author Seimon, Tracie A.
Kim, Mi-Jeong
Blumenthal, Antje
Koo, Jovanka
Ehrt, Sabine
Wainwright, Helen
Bekker, Linda-Gail
Kaplan, Gilla
Nathan, Carl
Tabas, Ira
Russell, David G.
Title Induction of ER stress in macrophages of tuberculosis granulomas
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2010-09
Sub-type Article (original research)
DOI 10.1371/journal.pone.0012772
Open Access Status DOI
Volume 5
Issue 9
Start page e12772.1
End page e12772.12
Total pages 12
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Collection year 2011
Language eng
Formatted abstract
The endoplasmic reticulum (ER) stress pathway known as the Unfolded Protein Response (UPR) is an adaptive survival pathway that protects cells from the buildup of misfolded proteins, but under certain circumstances it can lead to apoptosis. ER stress has been causally associated with macrophage apoptosis in advanced atherosclerosis of mice and humans. Because atherosclerosis shares certain features with tuberculosis (TB) with regard to lesional macrophage accumulation, foam cell formation, and apoptosis, we investigated if the ER stress pathway is activated during TB infection.

Principal Findings
Here we show that ER stress markers such as C/EBP homologous protein (CHOP; also known as GADD153), phosphorylated inositol-requiring enzyme 1 alpha (Ire1α) and eukaryotic initiation factor 2 alpha (eIF2α), and activating transcription factor 3 (ATF3) are expressed in macrophage-rich areas of granulomas in lungs of mice infected with virulent Mycobacterium tuberculosis (Mtb). These areas were also positive for numerous apoptotic cells as assayed by TUNEL. Microarray analysis of human caseous TB granulomas isolated by laser capture microdissection reveal that 73% of genes involved in the UPR are upregulated at the mRNA transcript level. The expression of two ER stress markers, ATF3 and CHOP, were also increased in macrophages of human TB granulomas when assayed by immunohistochemistry. CHOP has been causally associated with ER stress-induced macrophage apoptosis. We found that apoptosis was more abundant in granulomas as compared to non-granulomatous tissue isolated from patients with pulmonary TB, and apoptosis correlated with CHOP expression in areas surrounding the centralized areas of caseation.

In summary, ER stress is induced in macrophages of TB granulomas in areas where apoptotic cells accumulate in mice and humans. Although macrophage apoptosis is generally thought to be beneficial in initially protecting the host from Mtb infection, death of infected macrophages in advanced granulomas might favor dissemination of the bacteria. Therefore future work is needed to determine if ER-stress is causative for apoptosis and plays a role in the host response to infection.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
UQ Diamantina Institute - Open Access Collection
UQ Diamantina Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 46 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 52 times in Scopus Article | Citations
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Created: Thu, 10 Mar 2011, 10:02:09 EST