Dendritic Cells from Aged Subjects Display Enhanced Inflammatory Responses toChlamydophila pneumoniae

Abstract

Chlamydophila pneumoniae (CPn) is a common respiratory pathogen that causes a chronic and persistent airway infection. The elderly display an increased susceptibility and severity to this infection. However, the underlying mechanisms are not well understood. Dendritic cells (DCs) are the initiators and regulators of immune responses. Therefore, we investigated the role of DCs in the age-associated increased CPn infection in vitro in humans. Though the expression of activation markers was comparable between the two age groups, DCs from aged subjects secreted enhanced levels of proinflammatory mediators such as TNF-α and CXCL-10 in response to CPn. In contrast, the secretion of IL-10 and innate interferons, IFN-α and IFN-λ, was severely impaired in DCs from aged donors. The increased activation of DCs from aged subjects to CPn also resulted in enhanced proliferation of CD4 and CD8 T cells in a DC-T coculture. Furthermore, T cells primed with CPn-stimulated DCs from aged subjects secreted increased levels of IFN-γ and reduced levels of IL-10 compared to DCs obtained from young subjects. In summary, DCs from the elderly displayed enhanced inflammatory response to CPn which may result in airway remodeling and increase the susceptibility of the elderly to respiratory diseases such as asthma.

Role of Dendritic Cells in Inflammation and Loss of Tolerance in the Elderly

“…We also observed similar increase in these mediators in response to Chlamydophila pneumoniae (34). This increase was attributed to decrease in signaling via the PI3kinase/Akt pathway, which functions as a negative regulator of TLR signaling.…”

“…In contrast to mDCs in circulation, we have observed that MoDCs display increased secretion of pro-inflammatory cytokines TNF-α, CXCL-10, and IL-6 in response to TLR4 ligand, LPS ( 21 ). We also observed similar increase in these mediators in response to Chlamydophila pneumoniae ( 34 ). This increase was attributed to decrease in signaling via the PI3kinase/Akt pathway, which functions as a negative regulator of TLR signaling.…”

“…This decrease in IL-10 production may also contribute to loss of tolerance in aging. In addition to impaired IL-10 production, DCs from aged subjects also displayed a defect in the production of type I and III interferons in response to both influenza and Chlamydophila ( 34 , 36 ). The decrease in type I IFN production in older donors was also observed in MoDCs infected with West Nile virus ( 32 ).…”

Immunosenescence and human vaccine immune responses

“…Studies in humans have been primarily limited to MoDCs, while the expression of co-stimulatory molecules in DC subsets from the circulation and other tissues remains poorly understood. Despite maintaining their ability to express stimulatory molecules, current evidence suggests that MoDCs from older adults are less efficient at stimulating naïve CD4 + and CD8 + T cell proliferation and cytokine responses compared to MoDCs from younger subjects [69, 75, 81]. This has been attributed to the state of chronic inflammation observed among older adults, which could disrupt DC signaling and inhibit T cell activation.…”

Dendritic Cell-Airway Epithelial Cell Cross-Talk Changes with Age and Contributes to Chronic Lung Inflammatory Diseases in the Elderly

“…Furthermore, DCs from aged individuals, but not from young individuals, display an intrinsic defect in the production of interleukin-10 (IL-10), a potent anti-inflammatory cytokine that controls excessive production of pro-inflammatory mediators [ 20 ]. In addition, the secretion of protective cytokines in response to infections is impaired with aged DCs; DCs from aged individuals secrete reduced levels of Type-I-Interferons (IFNs) and Type III IFNs [ 18 , 19 ] in response to influenza and Chlamydia pneumoniae [ 30 ]. Other studies have also reported reduced secretion of type I IFNs by plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) in response to viral infections [ 24 , 31 , 32 , 33 ].…”