Dr. Steven J. Ackerman
- PhD, McGill University, Montreal
- Faculty Positions: Harvard Medical School, Harvard University, Boston; Mayo Graduate School of Medicine, Mayo Clinic and Foundation, Rochester
- Postdoctoral: Mayo Clinic and Foundation, Rochester; Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia
Transcriptional regulation of hematopoietic (myeloid) development and granulocyte (eosinophil) lineage-specific gene expression. Molecular biology, structural biology (structure-function relationships) and biologic activities of eosinophil-derived enzymes (phospholipases, lysophospholipases), granule cationic proteins/cytotoxins, and galectins as mediators of eosinophil effector function in allergic inflammation, tissue damage and disease pathogenesis. Eosinophil effector functions in inflammation, tissue remodeling, and fibrosis in asthma, allergy, and other eosinophil-associated diseases.
Our research interests center on the molecular biology, biochemistry and hematopoietic development of the human eosinophil leukocyte in health and disease pathogenesis. Ongoing research projects focus on the: (1) transcriptional mechanisms that regulate eosinophil development and lineage-specific gene expression in the process of commitment and terminal differentiation of multipotential myeloid progenitors to the eosinophil lineage, (2) molecular biology, biochemistry and biologic actions of granule and cytosolic enzymes and cationic cytotoxins expressed by eosinophils, and their roles in the effector functions of this granulocyte in disease pathogenesis, (3) structural biology (structure-activity relationships) of eosinophil granule-associated cytotoxins and enzyme mediators of inflammation, (4) cytokine regulation and mechanisms of eosinophil terminal differentiation, activation and secretion, including cytokine-activated signal transduction pathways, and (5) the roles of eosinophils and their mediators in normal tissue remodeling and pathological tissue fibrosis.
Recent work has included the cloning, sequencing and characterization of cDNA and genomic clones encoding eosinophil granule-associated proteins, isolation of the regulatory regions (promoters and enhancers) of these eosinophil-specific genes, and functional characterization of the cis-acting DNA elements and transcription factors that regulate their expression during eosinophil development and post-mitotic activation. We are characterizing the regulatory regions of the genes encoding the eosinophil-specific alpha (a) subunit of the IL-5 receptor (IL-5Ra), the eosinophil granule cationic proteins [major basic protein (MBP) and eosinophil peroxidase (EPO)], and the Charcot-Leyden crystal (CLC) protein (Galectin-10). These eosinophil promoters/enhancers are being analyzed as models for the differential regulation of myeloid specific genes in general, and eosinophil specific genes in particular, in the process of the commitment and differentiation of stem cells and multipotential bone marrow-derived progenitors to the granulocyte lineages. Transcription factors thus far shown to regulate eosinophil development and/or gene expression that are under investigation include members of the C/EBP family (a , ß, e and e isoforms), GATA-binding proteins and their co-activators/co-repressors [Friend of GATA (FOGs)], members of the ets family of transcriptional regulators including PU.1 and GA-binding protein (GABP), members of the Egr family, and the RFX family of transcriptional regulators. We are particularly interested in the functional interactions of transcriptional regulators such as the C/EBPs, GATA-binding proteins (GATA-1 and 2) and PU.1 in terms of their interactions (antagonism versus synergy) on target genes in the eosinophil compared to other myeloid lineages, and the enhancer roles of the RFX and RFX-associated proteins in IL-5 receptor expression. As well, we are characterizing novel signal transduction pathways mediated via IL-5/IL-5R signaling in the eosinophil, and the mechanisms that regulate expression of the soluble versus transmembrane isoforms of the receptor.
Our work on eosinophil function focuses primarily on the pro-inflammatory effector roles of eosinophils and their unique granule cationic proteins and lipolytic enzymes in the pathogenesis of asthma, allergic and other eosinophil-associated diseases and hypereosinophilic syndromes. Research on the cytotoxic and inflammatory effector functions of eosinophils includes the expression of recombinant eosinophil proteins (CLC/galectin-10, proMBP and MBP, eosinophil lysophospholipases) and analyses of structure-function relationships for their unique enzymatic and non-enzymatic activities using site-directed mutagenesis and molecular modeling based on crystallographic 3D structure. Additional projects include investigations of the mechanisms for eosinophil activation and secretion of these mediators in response to eosinophil-active cytokines and other physiologic stimuli. Related projects characterizing eosinophil effector mechanisms in the pathophysiology of asthma and other allergic diseases include studies of the mechanisms by which eosinophils induce airways dysfunction, fibroblast and epithelial cell activation, and the production of inflammatory cytokines and other mediators of tissue remodeling and pathological tissue fibrosis in the lung, gastrointestinal tract and other tissues. In this regard, we have recently developed a model of eosinophil-fibroblast interactions in which eosinophil products, including TGFß1 and other soluble mediators, induce fibroblast activation and secretion of fibrogenic cytokines such as IL-6, and the upregulation of genes involved in extracellular matrix homeostasis.
Aceves SS and Ackerman SJ. Relationships Between Eosinophilic Inflammation, Tissue Remodeling and Fibrosis in Eosinophilic Esophagitis. Immunol Allergy Clin N Am 2009; 29;197–211.
PMCID: PMC2665721. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665721/
Bedi R, Du J, Sharma AK, Gomes I and Ackerman SJ. Human C/EBPε activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood 2009; 113:317-327. PMCID: PMC2615649. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2615649/
Kagalwalla AF, Akhtar N, Woodruff SA, Rea B, Masterson JC, Mukkada V, Parashette KR, Du J, Fillon S, Protheroe CA, Lee JJ, Amsden K, Melin-Aldana H, Capocelli KE, Furuta GT and Ackerman SJ. Eosinophilic Esophagitis: Epithelial Mesenchymal Transition Contributes to Esophageal Remodeling and Reverses with Treatment. J. Allergy Clin. Immunol. 2012; 129(5):1387-1396. PMID: 22465212.
Furuta GT, Kagalwalla AF, Lee JJ, Alumkal P, Maybruck BT, Fillon S, Masterson JC, Ochkur S, Protheroe C, Moore W, Pan Z, Amsden K, Robinson Z, Capocelli K, Mukkada V, Atkins D, Fleischer D, Hosford L, Kwatia MA, Schroeder S, Kelly C, Lovell M, Melin-Aldana H, Ackerman SJ. The esophageal string test: a novel, minimally invasive method measures mucosal inflammation in eosinophilic esophagitis. Gut. 2012 Aug 15. [Epub ahead of print] PMID: 22895393. http://gut.bmj.com/content/early/2012/08/14/gutjnl-2012-303171.long