Julie Ledford

Julie Ledford

Associate Professor, Cellular and Molecular Medicine
Associate Professor, Immunobiology
Associate Professor, Medicine
Associate Professor, Clinical Translational Sciences
Associate Professor, Applied BioSciences - GIDP
Member of the Graduate Faculty
Associate Professor, BIO5 Institute
Primary Department
Contact
(520) 626-0276

Work Summary

Julie Ledford's research focuses on respiratory disease, and genetic and molecular mechanisms of allergic airway diseases in children.

Research Interest

Dr. Ledford’s current work in the area of pulmonary surfactant immunobiology combines her knowledge of mouse genetics, pulmonary disease models and immune function regulation and focuses on understanding the role of Surfactant Protein-A (SP-A) and how it regulates signaling pathways within various immune cell populations. Specifically, she is interested in how SP-A regulates degranulation, either directly or indirectly, of two important cell types in asthma: mast cells and eosinophils. More recently, Dr. Ledford’s research has focused on understanding how genetic variation within human SP-A2 alters functionality of the protein in relation to eosinophil activities and how this translates to characteristics observed in human asthma.

Publications

Holmer, S. M., Evans, K. S., Asfaw, Y. G., Saini, D., Schell, W. A., Ledford, J. G., Frothingham, R., Wright, J. R., Sempowski, G. D., & Perfect, J. R. (2014). Impact of surfactant protein D, interleukin-5, and eosinophilia on Cryptococcosis. Infection and immunity, 82(2), 683-93.

Cryptococcus neoformans is an opportunistic fungal pathogen that initiates infection following inhalation. As a result, the pulmonary immune response provides a first line of defense against C. neoformans. Surfactant protein D (SP-D) is an important regulator of pulmonary immune responses and is typically host protective against bacterial and viral respiratory infections. However, SP-D is not protective against C. neoformans. This is evidenced by previous work from our laboratory demonstrating that SP-D-deficient mice infected with C. neoformans have a lower fungal burden and live longer than wild-type (WT) control animals. We hypothesized that SP-D alters susceptibility to C. neoformans by dysregulating the innate pulmonary immune response following infection. Thus, inflammatory cells and cytokines were compared in the bronchoalveolar lavage fluid from WT and SP-D(-/-) mice after C. neoformans infection. Postinfection, mice lacking SP-D have reduced eosinophil infiltration and interleukin-5 (IL-5) in lung lavage fluid. To further explore the interplay of SP-D, eosinophils, and IL-5, mice expressing altered levels of eosinophils and/or IL-5 were infected with C. neoformans to assess the role of these innate immune mediators. IL-5-overexpressing mice have increased pulmonary eosinophilia and are more susceptible to C. neoformans infection than WT mice. Furthermore, susceptibility of SP-D(-/-) mice to C. neoformans infection could be restored to the level of WT mice by increasing IL-5 and eosinophils by crossing the IL-5-overexpressing mice with SP-D(-/-) mice. Together, these studies support the conclusion that SP-D increases susceptibility to C. neoformans infection by promoting C. neoformans-driven pulmonary IL-5 and eosinophil infiltration.

Mitsuhashi, A., Goto, H., Kuramoto, T., Tabata, S., Yukishige, S., Abe, S., Hanibuchi, M., Kakiuchi, S., Saijo, A., Aono, Y., Uehara, H., Yano, S., Ledford, J. G., Sone, S., & Nishioka, Y. (2013). Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages. The American journal of pathology, 182(5), 1843-53.

Surfactant protein A (SP-A) is a large multimeric protein found in the lungs. In addition to its immunoregulatory function in infectious respiratory diseases, SP-A is also used as a marker of lung adenocarcinoma. Despite the finding that SP-A expression levels in cancer cells has a relationship with patient prognosis, the function of SP-A in lung cancer progression is unknown. We investigated the role of SP-A in lung cancer progression by introducing the SP-A gene into human lung adenocarcinoma cell lines. SP-A gene transduction suppressed the progression of tumor in subcutaneous xenograft or lung metastasis mouse models. Immunohistochemical analysis showed that the number of M1 antitumor tumor-associated macrophages (TAMs) was increased and the number of M2 tumor-promoting TAMs was not changed in the tumor tissue produced by SP-A-expressing cells. In addition, natural killer (NK) cells were also increased and activated in the SP-A-expressing tumor. Moreover, SP-A did not inhibit tumor progression in mice depleted of NK cells. Taking into account that SP-A did not directly activate NK cells, these results suggest that SP-A inhibited lung cancer progression by recruiting and activating NK cells via controlling the polarization of TAMs.

Takezaki, A., Kitamura, A., Setoguchi, Y., Itoh, Y., Ledford, J., Goto, H., Nishioka, Y., & Yasutomo, K. (2017). Notch-mediated necroptosis due to a mutation in SFTPA1 is a crucial driver for pulmonary fibrosis.. Nature Immunology.
Ledford, J. G., Addison, K. J., Foster, M. W., & Que, L. G. (2014). Eosinophil-associated lung diseases. A cry for surfactant proteins A and D help?. American journal of respiratory cell and molecular biology, 51(5), 604-14.

Surfactant proteins (SP)-A and SP-D (SP-A/-D) play important roles in numerous eosinophil-dominated diseases, including asthma, allergic bronchopulmonary aspergillosis, and allergic rhinitis. In these settings, SP-A/-D have been shown to modulate eosinophil chemotaxis, inhibit eosinophil mediator release, and mediate macrophage clearance of apoptotic eosinophils. Dysregulation of SP-A/-D function in eosinophil-dominated diseases is also not uncommon. Alterations in serum SP-A/-D levels are associated with disease severity in allergic rhinitis and chronic obstructive pulmonary disease. Furthermore, oligimerization of SP-A/-D, necessary for their proper function, can be perturbed by reactive nitrogen species, which are increased in eosinophilic disease. In this review, we highlight the associations of eosinophilic lung diseases with SP-A and SP-D levels and functions.

Ogawa, H., Ledford, J. G., Mukherjee, S., Aono, Y., Nishioka, Y., Lee, J. J., Izumi, K., & Hollingsworth, J. W. (2014). Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-β. Respiratory research, 15, 143.

Surfactant protein D (SP-D) can regulate both innate and adaptive immunity. Recently, SP-D has been shown to contribute to the pathogenesis of airway allergic inflammation and bleomycin-induced pulmonary fibrosis. However, in allergic airways disease, the role of SP-D in airway remodeling remains unknown. The objective of this study was to determine the contribution of functional SP-D in regulating sub-epithelial fibrosis in a mouse chronic house dust mite model of allergic airways disease.