title: Induction of ER stress in macrophages of tuberculosis granulomas.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York, United States of America. tseimon@wcs.org
authors.forename: Tracie A
authors.initials: TA
authors.lastname: Seimon
authors.forename: Mi-Jeong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Antje
authors.initials: A
authors.lastname: Blumenthal
authors.forename: Jovanka
authors.initials: J
authors.lastname: Koo
authors.forename: Sabine
authors.initials: S
authors.lastname: Ehrt
authors.forename: Helen
authors.initials: H
authors.lastname: Wainwright
authors.forename: Linda-Gail
authors.initials: LG
authors.lastname: Bekker
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
authors.forename: Ira
authors.initials: I
authors.lastname: Tabas
authors.forename: David G
authors.initials: DG
authors.lastname: Russell
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006099:Granuloma / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000502:physiology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014376:Tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D056811:Unfolded Protein Response
chemical_list: D051700:Activating Transcription Factor 3; D051742:Transcription Factor CHOP