Our laboratory is interested in the mechanisms by which polymorphonuclear leukocytes (neutrophils) are attracted to, and potentially injure, the lung. The lung has a unique architecture and physiology that results in a large number of neutrophils within the lung microcirculation under even normal circumstances. Following an inflammatory response in the lung, neutrophils are further recruited from the bone marrow into the circulation, and thence are avidly retained within the lung. We are interested in mechanisms of recruitment during inflammation, as well as the feedback loops that control neutrophil number under both homeostatic and inflammatory conditions.
Neutrophil number in the circulation is regulated in a complex fashion that senses neutrophil accumulation at a sentinel site, which we believe is the gut. Chemokine CXCL5 secretion by the gut epithelium attracts neutrophils, which are then sensed by phagocytic cells that secrete a variety of cytokines. Recognition of neutrophils is accompanied by decreased secretion of IL-l and IL-23, cytokines which drive differentiation of IL-17-producing cells. IL-17 in tum, then induces production of G-CSF and other CXC chemokines, thus contributing to release of neutrophils from the bone marrow. Somewhat surprisingly, the gut microbiome is involved in establishing the "setpoint" for these cytokines, and hence the neutrophil number. This complex feedback system is deranged in mice deficient in CXCL5, or the receptor for CXC chemokines, CXCR2. It is also abnormal in mice and humans deficient in CD18.
Within Neonatology, we are particularly interested in the period during which the neonate acquires its repertoire of microbes in the gut and other sites. We are interested in the idea that this process sets in motion this feedback mechanism, and thus may be critically important for the adaptation of neonates to a world containing microbes.
Education and Training
MD - Harvard Medical School, Boston, MA
Beth Israel Hospital, Boston, MA
Beth Israel Hospital, Boston, MA
Pulmonary Medicine - University of Colorado School of Medicine, Denver, CO
Critical Care MedicineInternal MedicinePulmonary Medicine
Titles and Academic Titles
Physician-Scientist in Neonatology
Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania
Departments and Services
Floros J, Londono D, Gordon D, Silveyra P, Diangelo SL, Viscardi RM, Worthen GS, Shenberger J, Wang G, Lin Z, Thomas NJ. IL-18R1 and IL-18RAP SNPs may be associated with bronchopulmonary dysplasia in African-American infants. Pediatr Res. 71(1):107-114, Jan 2012. PMC3610412
Mei J, Liu Y, Dai N, Hoffmann C, Hudock KM, Zhang P, Guttentag SH, Kolls JK, Oliver PM, Buslunan FD, Worthen GS. Cxcr2 and Cxcl5 regulate the IL-17/G-CSFaxis and neutrophil homeostasis in mice. J. Clin Invest. 122(3):974-986, Mar 2012. PMC3287232
Ramon H.E., Beal A., Liu Y, Worthen G.S., and P. M. Oliver. The E3 ubiquitin ligase adaptor Ndfip 1 regulates Th17 differentiation by limiting the production of proinflammatory cytokines. J ImmunoI. 188(8):4023-4031, Apr 2012. PMC3713491
Balamayooran G, Batra S, Cai S, Mei J, Worthen GS, Penn AL, Jeyaseelan S. Role of CXCL5 in leukocyte recruitment to the lungs during secondhand smoke exposure. 2012 Am J Resp Cell Mol BioI. 47(1):104-111, Ju12012. PMC3402800
Fridlender ZG, Sun J, Mishalian I, Singhal S, Cheng G, Kapoor V, Homg W, Fridlender Bayuh R, Worthen GS, Albelda SM. Transcriptomic analysis comparing tumor-associated neutrophils with granulocytic myeloid-derived suppressor cells and normal neutrophils. PLoS One. http://www.ncbi.nlm.nih.gov/pubmedI22348096 7(2):e31524, 2012. PMC3279406
Hudock KM, Liu Y, Mei J, Marino RC, Hale JE, Dai N, Worthen GS. Delayed resolution of lung inflammation in Il-1rn-/- mice reflects elevated IL-17/G-CSF expression. Am J Respir Cell Mol BioI. 47:436-444, Oct 2012. PMC3488622
Liu Y, Mei J. Gonzales L, Yang G, Dai N, Wang P, et al. IL-17A and TNF-α exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J Immunol. 2011 Mar 1;186(5):3197-205. Epub Jan 31. Cited in PubMed; PMID 21282514.
Fuentes R, Wang Y, Hirsch J, Wang C, Rauova L, Worthen GS. Infusion of mature megakaryocytes into mice yields functional platelets. J Clin Invest. 2010 Nov 1;120(11):3917-22. doi: 10.1172/JC143326. Epub 2010 Oct 25. Cited in PubMed; PMID 20972336.
Mei J, Liu Y, Dai N, Favara M, Greene T, Jeyaseelan S, et al. CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection. Immunity. 2010 Jul 23;3(1):106-17. Cited in PubMed; PMID 20643340.
Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009 Sep 8;16(3):183-94. Cited in PubMed; PMID 19732719.
Cai S, Zemans RL, Young SK, Worthen GS, Jeyaseelan S. Myeloid differentiation protein-2-dependent and -independent neutrophil accumulation during Escherichia coli pneumonia. Am J Respir Cell Mol Biol. 2009 Jun;40(6):701-9. Epub 2008 Nov 6.
Zemans RL, Briones N, Young SK, Malcolm KC, Refaeli Y, Downey GP, et al. A novel method for long term bone marrow culture and genetic modification of murine neutrophils via retroviral transduction. J Immunol Methods. 1009 Jan 30;340(2):102-15. Epub 2008 Nov 14. Cited in PubMed; PMID 19010330.
Editorial and Academic Positions
Academic and institutional committees
2009-present, IACUC, The Children's Hospital of Philadelphia
2013-present, Executive committee Center for Lung Biology, University of Pennsylvania
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