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Peter Henson BVM&S, PhD, MD

Distinguished Professor


 

 

 

 

Distinguished Professor
Integrated Department of Immunology and Department of Medicine,
Univesity of Colorado Denver and Department of Pediatrics, National Jewish Health
Phone: 303-398-1325
Email: hensonp@njhealth.org

 
Cell Biology of inflammation, innate immunity and apoptotic cell removal in relation to acute and chronic lung disease.
 
Our group has four major, interacting, areas of interest.
 
One focuses on the initiation, progression and in particular, resolution and mediator control of the inflammatory process, extending from the biochemical, molecular and cellular levels to animal systems and patient investigation.
 
A second emphasis is represented by our interest in apoptosis, and particularly the role of apoptotic cell recognition and removal. Surface structures on apoptotic cells (especially phospholipid species) are recognized by mononuclear phagocytes, dendritic cells and near-neighbor tissue cells) and contribute to processes of tissue homeostasis (cell removal and replacement) and remodeling, as well as in resolution and suppression of inflammation and modulation of adaptive immunity. These studies relate importantly to the pathogenesis of interstitial lung diseases (ILDs) and COPD as well as to normal repair after acute lung injury and inflammation (ALI). Animal and in vitro models for these processes are an important element of our investigative arsenal and experiments extend from, and to, human physiology, pathology and clinical investigation.
 
A unique form of phagocytosis appears responsible for removal of apoptotic cell and tissue debris from tissues. We have named this “efferocytosis” (from “effero” – to carry to the grave, to bury). It is highly conserved within all metazoa, significantly precedes (in evolutionary terms) “classic” phagocytosis driven by Fc or complement receptor ligation and can be carried out to various levels of efficiency in many mammalian cell types. Signaling, mechanisms, consequences and relation to innate, adaptive and auto-immunity represent an additional focus.
 
Innate immunity is mediated by groups of soluble or cell surface ligands for pathogen associated molecular patterns (PAMPs) or damage associated molecular patterns (DAMPs). It is now apparent that recognition of apoptotic or necrotic cells and cell debris shows significant similarities and consequences resulting in a delicate balance between anti- and pro-inflammatory responses and subsequent adaptive immunity.  Lung collectins are important regulators of these processes and remain a research interest in the context of the unique pulmonary environment.
 
Trainees working in our laboratory take on projects in all these areas from basic cell biology and biochemistry to animal models and translational studies leading into the clinic.
  • Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL and Henson PM. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol. 148(7):2207-2216, 1992.
  • Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFb, PGE2, and PAF. J. Clin. Invest. 101:890-898, 1998
  • Hoffmann PR, deCathelineau AM, Ogden CA, Leverrier Y, Bratton DL, Daleke DL, Ridley AJ, Fadok VA, Henson PM.  Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155(4):649-659, 2001.
  • Huynh, M-LN, Fadok VA, Henson PM. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF1 secretion and resolution of inflammation. J Clin Invest 109:41-50, 2002.
  • Teder P, Vandivier RW, Jiang D, Liang J, Pure E, Henson PM, Noble PW. Resolution of lung inflammation by CD44. Science 296(5565):155-158, 2002.
  • Gardai SJ, Xiao Y-Q, Dickinson M, Nick J, Voelker D, Greene K, Henson P. By binding SIRP or calreticulin/CD91, lung collectins act as dual function surveillance molecules to suppress or enhance inflammation. Cell. 115:13-23, 2003.
  • Gardai S.J, McPhillips KA, Frasch SC, Janssen W.J, Starefeldt A, Murphy-Ullrich JE, Bratton DL, Oldenborg PA, Michalak M, Henson PM. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:321-334, 2005.
  • Freire-de-Lima CG, Xiao YQ, Gardai SJ, Bratton DL, Schiemann WP, Henson PM. Apoptotic cells, through transforming growth factor-, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J Biol Chem 2006, 281(50):38376-38384, 2006
  • McPhillips K, Janssen W.J, Ghosh M, Byrne A, Gardai S, Remigio L, Bratton, DL, Kang JL, Henson P. TNF-alpha inhibits macrophage clearance of apoptotic cells via cytosolic phospholipase A2 and oxidant-dependent mechanisms. J Immunol 178:8117-8126, 2007. PMID: 17548650.
  • Frasch SC, Zemski Berry K, Fernandez-Boyanapalli R, Jin H-S, Leslie, C, Henson, PM, Murphy RC, Bratton DL. NADPH oxidase-dependent generation of lyso-phosphatidylserine enhances clearance of activated and dying neutrophils via G2A. J Biol Chem. Nov 28;283(48):33736-49. 2008. PMID: 18824544,
  • Vandivier RW, Richens TR, Horstmann SA, Decathelineau AM, Ghosh M, Reynolds SD, Xiao YQ, Riches DW, Plumb JD, Vachon E, Downey GP, Henson PM. Dysfunctional cystic fibrosis transmembrane conductance regulator inhibits phagocytosis of apoptotic cells with pro-inflammatory consequences. Am J Physiol Lung Cell Mol Physiol 297(4): L677-86, 2009. PMID: 19633071.
  • Frasch SC, Fernandez-Boyanapalli RF, Zemski Berry K, Leslie CC, Bonventre JV, Murphy RC, Henson PM, Bratton DL. Signaling via macrophage G2A enhances efferocytosis of dying neutrophils by augmentation of Rac activity. J Biol Chem. 286(14):12108-22, 2011. PMID: 21297111
  • Janssen WJ, Barthel L, Muldrow A, Oberley-Deegan RE, Kearns MT, Jakubzick C, Henson PM. Fas determines differential fates of resident and recruited macrophages during resolution of acute lung injury. Am J Respir Crit Care Med. 184(5):547-60.2011. PMID:21471090
  • Desch A.N., Randolph G.J., Murphy K., Gautier E.L., Kedl R.M., Lahoud M.H., Caminschi I., Shortman K., Henson P.M. and Jakubzick C.V. (2011). CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen. J Exp Med 208(9): 1789-97. PMID: 21859845 PMCID: PMC3171085
  • Cole C., Thomas S., Filak H., Henson P.M. and Lenz L.L. Nitric Oxide Increases Susceptibility of Toll-like Receptor-Activated Macrophages to Spreading Listeria monocytogenes. Immunity 36(5): 807-20, 2012
  • Frasch SC, Fernandez-Boyanapalli R, Zemski Berry K, Murphy RC, Leslie CC, Henson PM, Bratton DL. Neutrophils regulate tissue neutrophilia in inflammation via the oxidant modified lipid lysophosphatidylserine. J Biol Chem. 2013 Feb 15;288(7):4583-93. doi: 10.1074/jbc.M112.438507. PMID:23293064
  • Jakubzick C, Gautier E, Gibbings SL, Sojka DK, Schlitzer A, Johnson TE, Ivanov S, Duan Q, Bala S, Condon T, van Rooijen N, Grainger JR, Belkaid Y, Ma’ayan A, Riches DW, Yokoyama WM, Ginhoux F, Henson PM, Randolph GJ. Minimal differentiation of classical monocytes as they survey steady state tissues and transport antigen to lymph nodes. Immunity. In press. 2013.