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Tomás Patrick Carroll, PhD

Immune cell function in Alpha-1-Antitrypsin Deficiency

Alpha-1-Antitrypsin (AAT) is synthesized in the liver and functions as the most important antiprotease in the lung. AAT Deficiency (AATD) is a hereditary disorder resulting from mutations in the AAT gene and presents with emphysema in young adults and liver disease in childhood. The most common form of AAT Deficiency is caused by the Z mutation encoding a glutamine to lysine substitution at position 342 of the AAT protein. This causes the protein to fold aberrantly and accumulate in the endoplasmic reticulum (ER). The liver disease is believed to be associated with intracellular accumulation of AAT in the ER leading to ER stress responses. The lung disease, on the other hand, is due to decreased levels of the AAT antiprotease in the airways, thereby facilitating proteolytic damage. In addition to hepatocytes, AAT is also synthesized by monocytes, neutrophils, and epithelial cells. We set out to investigate whether ER accumulation of Z AAT in monocytes will impact specific phenotypes and functions of these immune cells, thus contributing to the overall inflammatory disease process. In the present study we show for the first time that the unfolded protein response (UPR) is activated in monocytes of ZZ individuals. ATF4, XBP-1 and a subset of genes involved in the UPR are activated in monocytes of ZZ compared to MM individuals. We have also demonstrated that monocytes from ZZ individuals are intrinsically more pro-inflammatory and produce increased levels of cytokines compared to monocytes from MM individuals. We conclude that the activation of the UPR within monocytes may impair normal function and contribute to the pro-inflammatory milieu in the AATD lung.

Research and professional experience:
 
February 2004 - Department of Respiratory Research, RCSI ERC Beaumont, Post-doctoral fellowship

This post is funded by the Department of Health and Children and the Alpha-1 Foundation, and involves basic research into the molecular mechanisms underlying several inflammatory lung diseases, particularly Alpha-1-Antitrypsin deficiency.
October 2000 -
January 2004		 Department of Respiratory Research, RCSI Beaumont, PhD Student. Thesis entitled "Interleukin-1 and Neutrophil Elastase: Key Pro-inflammatory Stimuli Regulating Inflammation in Cystic Fibrosis".
May - August 2000 National Diagnostic Centre, NUI Galway, Research Student
January - March 1999 Biochemistry Department, NUI Galway, Research Student
May - August 1998 Yamanouchi Research Institute, Oxford, England, Research Student


Publications:
  1. Griffin S, Carroll TP, Greene CM, O'Neill SJ, Taggart CC, and McElvaney NG. Effect of pro-inflammatory stimuli on mucin expression and inhibition by secretory leucoprotease inhibitor. Cell. Microbiol. 2007 Mar;9(3):670-9.
  2. Carroll TP, Greene CM, Taggart CC, Bowie AG, O'Neill SJ, McElvaney NG. Viral inhibition of interleukin-1- and neutrophil elastase-induced inflammatory responses in bronchial epithelial cells. J Immunol. 2005 Dec 1;175(11):7594-601.
  3. Taggart CC, Greene CM, Carroll TP, O'Neill SJ, McElvaney NG. Elastolytic proteases: inflammation resolution and dysregulation in chronic infective lung disease. Am J Respir Crit Care Med 2005 May 15;171(10):1070-6.
  4. Greene CM, Carroll TP, Smith SG, Taggart CC, Devaney J, Griffin S, O'Neill SJ, McElvaney NG. TLR-induced inflammation in cystic fibrosis and non-cystic fibrosis airway epithelial cells. J Immunol. 2005 Feb 1;174(3):1638-46.
  5. Carroll T, Greene C, Taggart C, McElvaney N, O'Neill S. Interleukin-1, neutrophil elastase and lipopolysaccharide: Key pro-inflammatory stimuli regulating inflammation in cystic fibrosis. Curr Resp Med Rev 2005; 1: 43-67
  6. Devaney JM, Greene CM, Taggart CC, Carroll TP, O'Neill SJ, McElvaney NG. Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4. FEBS Lett. 2003 Jun 5;544(1-3):129-32.
  7. Walsh DE, Greene CM, Carroll TP, Taggart CC, Gallagher PM, O'Neill SJ, McElvaney NG. Interleukin-8 up-regulation by neutrophil elastase is mediated by MyD88/IRAK/TRAF-6 in human bronchial epithelium. J Biol Chem 2001 Sep 21; 276(38): 35494-9.

Contact
Tomás Patrick Carroll, PhD
Respiratory Research Divsion –
Royal College of Surgeons in Ireland
Education and Research Centre
Beaumont Hospital
Beaumont Road
9 Dublin
Ireland
Telephone: +353 (1) 8093800
Fax: +353 (1) 8093808
E-mail: tcarroll@rcsi.ie