Apoptosis and cell clearance: Molecular mechanisms and implications for human disease
Apoptosis is a highly regulated process of cell deletion and plays a fundamental role in the maintenance of tissue homeostasis in the adult organism. Many human diseases can be attributed directly or indirectly to a derangement of apoptosis, resulting in either cell accumulation, in which cell eradication or cell turnover is impaired, or cell loss, in which the apoptotic program is inadvertently triggered (Fadeel & Orrenius, J. Intern. Med., 2005; Fadeel, et al., Cell Death Differ., 2008). Moreover, defective macrophage engulfment and degradation of cell corpses may also contribute to a dysregulation of tissue homeostasis (Fadeel & Xue, Crit. Rev. Biochem. Mol. Biol., 2009; Fadeel, Xue, Kagan, Biochem. Biophys. Res. Commun. 2010).
One of our main areas of interest is to understand the molecular regulation of cell death and cell clearance by cells of the immune system and the relevance of these processes in chronic inflammation and autoimmune disease (principal funding: Swedish Research Council: Senior Investigator Award; and Karolinska Institutet: Strategic Professorship). We coined the term programmed cell clearance to describe the process of macrophage recognition and disposal of apoptotic cells in order to emphasize that this is a genetically regulated and evolutionarily conserved process. We are currently aiming to dissect the mechanism of macrophage clearance not only of apoptotic cells but also the disposal of organelles or other subcellular structures that are released from dying cells under various pathological conditions and which could act as danger signals to activate inadvertent immune responses. We are engaged in long-standing collaborations with several other researchers including Prof. Valerian Kagan (University of Pittsburgh) and Prof. Ding Xue (University of Colorado).
Molecular and clinical studies of severe congenital neutropenia or Kostmann disease
Our research interests also include cancer research with focus on apoptosis signaling in malignant and non-malignant (pre-malignant) hematological diseases, such as severe congenital neutropenia (SCN) or Kostmann disease, and hematopoietic malignancies such as leukemia, lymphoma, and myeloma (principal funding: Swedish Cancer Research Foundation and Stockholm County Council (ALF Project). We actively collaborate with clinical colleagues at the Karolinska University Hospital and with several other national and international researchers in Europe and the United States.
In particular, we have contributed to the identification of mutations in the gene encoding HS-1-associated protein X-1 (HAX-1) in patients with autosomal recessive forms of Kostmann disease, a condition that was first described by the Swedish pediatrician, Dr. Rolf Kostmann, in the 1950s. We have shown that myeloid precursors from these patients undergo accelerated, mitochondria-dependent apoptosis. More recent studies are beginning to unravel a prominent role for HAX-1 in apoptosis signaling not only in the hematopoietic compartment, but also in the central nervous system. Moreover, several different cellular and viral binding partners of HAX-1 have been identified thus pointing toward a complex and multifunctional role of this protein (Fadeel & Grzybowska, Biochem Biophys Acta, 2009). We recently reported that HAX-1 is overexpressed in certain forms of B lymphoma and we are now aiming to delineate the role of HAX-1 in hematopoietic malignancies.
Our research also aims to identify novel gene defects in SCN patients of unknown genetic etiology. The latter studies are performed in part in collaboration with the Science for Life Laboratory.
Engineered nanomaterials: Toxicological studies and biomedical implications
Engineered nanomaterials have unique physico-chemical properties that make them promising for many technological and biomedical applications, including tissue regeneration, drug and gene delivery and in vivo imaging of disease processes. However, intentional as well as unintentional human exposures to engineered nanomaterials are set to increase, and this necessitates an increased understanding of the potential adverse effects on human health and the environment.
Nanotoxicology is an emerging discipline focused on understanding the properties of engineered nanomaterials and their interactions with biological systems, and may be viewed as the study of the undesirable interference between man-made nanomaterials and cellular nanostructures or nanomachines (Fadeel & Garcia-Bennett, Adv. Drug Deliv. Rev., 2010; Shvedova, Kagan, Fadeel, Annu. Rev. Pharmacol. Toxicol., 2010; Feliu & Fadeel, Nanoscale, 2010; Fadeel & Nyström, J Control Release, 2012).
Our research is currently focused on the interaction of engineered nanomaterials with the immune system, the primary defense system against foreign intrusion. Principal funding: Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS), Swedish Cancer and Allergy Foundation, and the European Commission. We are interested in molecular mechanisms of nanoparticle internalization and biodegradation, and we study mechanisms of cytotoxicity including the induction of programmed cell death (apoptosis), oxidative stress, and inflammation, and the role of the so-called corona of biomolecules (proteins, lipids) in regulation of nano-bio-interactions in vitro and in vivo. We are actively engaged in numerous international collaborations in the field of nanotoxicology including the FP7-MARINA project (managing risks of nanomaterials).
- Seventh Framework of the European Commission
- Swedish Research Council
- Swedish Cancer Foundation
- Swedish Childrens Cancer Foundation
- Swedish Council for Working Life and Social Research
- Stockholm County Council (ALF project)
- Seventh Framework of the European Commission
- Govind Gupta, postdoctoral researcher
- Sandeep Keshavan, postdoctoral researcher
- Mathilde Delaval, postdoctoral researcher
- Guotao Peng, postdoctoral researcher
- Carmine Cerrato, postdoctoral researcher
Five selected publications
Feliu N, Walter MV, Montanez MI, Kunzmann A, Hult A, Nyström A, Malkoch M, Fadeel B. (2012)
Stability and biocompatibility of a library of polyester dendrimers in comparison to polyamidoamine dendrimers.
Biomaterials. 2012 Mar;33(7):1970-81.
Kagan VE, Konduru NV, Feng W, Allen BL, Conroy J, Volkov Y, Vlasova II, Belikova NA, Yanamala N, Kapralov A, Tyurina YY, Shi J, Kisin ER, Murray AR, Franks J, Stolz D, Gou P, Klein-Seetharaman J, Fadeel B, Star A, Shvedova AA. (2010)
Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation.
Nat Nanotechnol. 2010 May;5(5):354-9.
Sanmun D, Witasp E, Jitkaew S, Tyurina YY, Kagan VE, Åhlin A, Palmblad J, Fadeel B. (2009)
Involvement of a functional NADPH oxidase in neutrophils and macrophages during programmed cell clearance: implications for chronic granulomatous disease.
Am J Physiol Cell Physiol. 2009 Sep;297(3):C621-31.
Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, Rathinam C, Boztug K, Schwinzer B, Rezaei N, Bohn G, Melin M, Carlsson G, Fadeel B, Dahl N, Palmblad J, Henter JI, Zeidler C, Grimbacher B, Welte K. (2007)
HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).
Nat Genet. 2007 Jan;39(1):86-92.
Henter JI, Karlen J, Calming U, Bernstrand C, Andersson U, Fadeel B. (2001)
Successful treatment of Langerhans cell histiocytosis with etanercept.
N Engl J Med. 2001 Nov 22;345(21):1577-8.
Bengt Fadeel, Antonio Pietroiusti, Anna Shvedova
Adverse Effects of Engineered Nanomaterials: Exposure, Toxicology and Impact on Human Health (Elsevier, 2012)