Advisory Committee Chair
Carlos J Orihuela
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Lower respiratory infections are the primary cause of infectious death among the elderly. One reason for this is ‘inflamm-aging,’ a chronic low-grade inflammatory state that develops with advanced age. Pertinently, our group has shown increases in TNF levels to be responsible for age-dependent macrophage dysfunction (ADMD) and, in turn, enhanced susceptibility to Streptococcus pneumoniae, the leading cause of community-acquired pneumonia. The underlying molecular mechanisms responsible, however, remain unclear. Following adoptive transfer of alveolar macrophages (AM) from aged (18+ months) or young (3-6 month) mice into young mice, followed by infection with S. pneumoniae, we found that aged AM were sufficient to increase susceptibility to lower respiratory tract infection and invasive disease. RNAseq of AM isolated from young and aged mice in wildtype and TNF KO backgrounds revealed decreased expression of MAPK regulated genes as a result of aging and TNF exposure. We then identified two phosphatases, Dusp1 and Ptprs, known to act as negative regulators of MAPK signaling, that were upregulated with increased age in TNF-dependent manner. Pharmacological downregulation of these molecules with TNF antibody offered some protection against invasive disease while upregulation using dexamethasone was sufficient to induce defects in macrophage function and increase the burden of disease. Macrophage-like cell line, J774.1, transduced to overexpress these negative regulators suppressed the activation of MAPK associated-cell signaling. Likewise, Dusp1 and Ptprs knockout J7741.1 cells, created using CRISPR, did not develop an ADMD phenotype even when exposed to TNF. Our results indicate that increased expression of homeostatic regulators of cellular activation during aging, as a result of chronic exposure to TNF, suppresses the ability of AM to adequately respond to infection and this contributes to the increased susceptibility to pneumonia seen in the elderly.
Kruckow, Katherine Lauren, "Characterizing The Role Of Mapk Phosphatases In Age-Dependent Macrophage Dysfucntion And Increased Suceptiblity To Pneumonia In A Tnf-Dependent Manner" (2023). All ETDs from UAB. 3510.
Available for download on Friday, December 27, 2024