Antonello Punturieri, M.D., Ph.D.
Research Investigator
Department of Internal Medicine
Division of Pulmonaryand Critical Care Medicine

pantonel@umich.edu

Sepsis and septic shock are the 13th most common cause of death in the United States. In the pulmonary setting of the disease, both Gram negative (P. Aeruginosa) and Gram positive ( S. Aureus) bacteria account for more than 40% of the responsible pathogens. Upon encounter with a microorganism, the first line of defense and ultimately the cells that are responsible for determining the quality/quantity of the immune response are resident macrophages. In the lung, inhaled particles and microorganisms daily challenge alveolar macrophages, without immediate deleterious effects for the body. Only upon the insurgence of a possible dangerous situation, alveolar macrophages will start an immune response using as tools for the recognition of potentially pathogenic organisms, innate immune receptors.

We are currently characterizing at the biochemical and biological level several of the receptors involved in the innate immune response in the lung. In particular our studies focus on the role of Toll-Like Receptors (TLRs) and other members of the Leucin-Rich Repeat (LRR) family of receptors in the recognition and processing of bacterial-derived structures. We have recently analyzed, in a mouse in vitro system, the differential response to the same bacterial-derived structures by resident macrophage populations from different body locations. Alveolar macrophages, in particular, appear to have a higher threshold level for response. This is mainly achieved by down-regulation of several LRR proteins, namely TLR4 and CD14.

Understanding the biochemical and cellular events that lead to normal or dis-regulated response may ultimately lead to the development of tools for the screening of subjects at higher risk for the insurgence of septic shock and associated syndromes.

Representative Publications

Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C. Mutations of CTSK result in pycnodysostotsis via a reduction in cathepsin K protein. J Bone Mineral Res 14: 1649-1653, 1999.

Hotary K, Allen E, Punturieri A, Yana I, Weiss SJ. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2 and 3. J Cell Biol 6: 1309-1323, 2000.

Hu B, Sonstein J, Christensen PJ, Punturieri A, Curtis JL. Deficient in vitro and in vivo phagocytosis of apoptotic T cells by resident murine alveolar macrophages. J Immunol 165: 2124-2133, 2000.

Punturieri A, Filippov S, Allen ED, Caras I, Murray R, Reddy V, Weiss SJ. Regulation of elastynolitic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages. J Exp Med 192: 789-799, 2000.

Hu B, Punturieri A, Todt J, Sonstein J, Polak T, Curtis JL. Phagocytosis of apoptotic T cells by resident murine tissue macrophages requries multiple signal transduction events. J Leuk Biol 71 (5):881-9, 2002 .

Hu B, Punturieri A, Todt J, Sonstein J, Polak T, Curtis JL.
Recognition and phagocytosis of apoptotic T cells by resident murine tissue macrophages require multiple signal transduction events. J Leukoc Biol May; 71(5):881-889, 2002.

Todt JC, Hu B, Punturieri A, Sonstein J, Polak T, Curtis JL.
Activation of protein kinase C beta II by the stereo-specific phosphatidylserine receptor is required for phagocytosis of apoptotic thymocytes by resident murine tissue macrophages.J Biol Chem Sep 27; 277(39):35906-35914, 2002.

Mor-Vaknin N, Punturieri A, Sitwala K, Markovitz DM.. Vimentin is secreted by activated macrophages. Nat Cell Biol Jan; 5(1): 59-63, 2003.
Curtis JL, Punturieri A. Enhancing antitumor immunity perioperatively. A matter of timing, cooperation, and specificity. Am J Respir Cell Mol Biol, May; 28(5): 541-545, 2003.

Punturieri, A., R. S. Alviani, T. Polak, P. Copper, J. Sonstein and J. L. Curtis (2004). "Specific engagement of TLR4 or TLR3 does not lead to IFN-beta-mediated innate signal amplification and STAT1 phosphorylation in resident murine alveolar macrophages." J Immunol 173(2): 1033-42.