Abstract
The age-associated decline of immune responses causes high susceptibility to infections and reduced vaccine efficacy in the elderly. However, the mechanisms underlying age-related deficits are unclear. Here, we found that the expression and signaling of flagellin (FlaB)-dependent Toll-like receptor 5 (TLR5), unlike the other TLRs, were well maintained in old macrophages, similar to young macrophages. The expression and activation of TLR5/MyD88, but not TLR4, were sensitively regulated by the upregulation of caveolin-1 in old macrophages through direct interaction. This interaction was also confirmed using macrophages from caveolin-1 or MyD88 knockout mice. Because TLR5 and caveolin-1 were well expressed in major old tissues including lung, skin, intestine, and spleen, we analyzed in vivo immune responses via a vaccine platform with FlaB as a mucosal adjuvant for the pneumococcal surface protein A (PspA) against Streptococcus pneumoniae infection in young and aged mice. The FlaB-PspA fusion protein induced a significantly higher level of PspA-specific IgG and IgA responses and demonstrated a high protective efficacy against a lethal challenge with live S. pneumoniae in aged mice. These results suggest that caveolin-1/TLR5 signaling plays a key role in age-associated innate immune responses and that FlaB-PspA stimulation of TLR5 may be a new strategy for a mucosal vaccine adjuvant against pneumococcal infection in the elderly.
Highlights
Individuals exhibit a decreased ability to resist infectious diseases and generate robust, protective immune responses against vaccinepreventable diseases, including influenza and pneumonia (Boraschi et al, 2010; Goronzy & Weyand, 2013)
We examined the levels of ligand-specific Toll-like receptors (TLRs)-dependent proinflammatory cytokines, including IL-1b, IL-6 and TNF-a, after treatment with Salmonella extracts (Sal-P), which can induce the activation of several types of TLRs; LPS activated TLR4, and FlaB activated Toll-like receptor 5 (TLR5) in the macrophages from young and aged mice
To elucidate the FlaB-dependent TLR5 activation in aging, we evaluated the expression of TLR5, with TLR4 as a negative control, in the macrophages from young and aged mice
Summary
Individuals exhibit a decreased ability to resist infectious diseases and generate robust, protective immune responses against vaccinepreventable diseases, including influenza and pneumonia (Boraschi et al, 2010; Goronzy & Weyand, 2013). The T- and B-lymphocyte compartments of the adaptive immune system are known to progressively deteriorate with advancing age (Geiger & Rudolph, 2009; Palmer, 2013), the impact of aging on the innate immune system remains unclear. Toll-like receptors (TLRs) play a crucial role as pattern recognition receptors in signaling danger and initiating the host innate responses. TLR5 is stimulated by flagellin, the major structural component of bacterial flagella. Both human TLR5 and mouse TLR5 recognize similar molecular determinants of flagellin from various bacteria
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