Toll-like Receptor function of murine macrophages, probed by cytokine induction, is biphasic and is not impaired globally with age

• Immunosenescence reflects the dysregulation of diverse immune activities.
• Macrophages have been implicated, but the role of TLR alterations is contentious.
• We find no global alterations of intrinsic macrophage TLR responsiveness with age.
• Macrophages exhibit an intriguing, aging-independent, binary response behavior.
• Widespread TLR alterations do not account for immunosenescent inflammatory status.

Aging is associated with a waning of normal immune function. This “immunosenescence” is characterized by a diverse repertoire of seemingly discreet and unbalanced immune alterations. A number of studies have suggested that aging-associated alterations in innate immune responsiveness, especially responsiveness dependent on Toll-like Receptor (TLR) engagement, are causally involved. We find, however, that the magnitude and dose-dependency of responsiveness to TLR engagement (assessed with respect to cytokine production) in distinct populations of murine macrophages are not altered generally with animal age or as a consequence of immunosenescence. Responses elicited with a wide array of TLR agonists were examined by extensive functional analyses, principally on the level of the individual cell. These studies reveal an intriguing “all-or-nothing” response behavior of macrophages, independent of animal age. Although reports to the contrary have been cited widely, aging-associated immune decline cannot be attributed to widespread alterations in the extents of TLR-dependent innate immune macrophage responses.