Chronic inflammation arises in aging for a variety of reasons. Researchers focused on immune system dysfunction refer to inflammaging, a state in which the immune system is both roused and ineffective. This is in part a result of the burden of persistent infection gained across a lifetime, but also a consequence of growing numbers of senescent cells. The immune system should be removing these cells, but progressively fails at that task also. Thus immune system failure feeds upon itself, accelerating like all aspects of age-related decline. Damage causes damage.
A more subtle consequence of continual inflammation is disruption of the normal processes of tissue maintenance and regeneration. Brief and localized inflammatory signaling is a necessary part of the normal operation of regenerative processes in youthful tissues, helping to guide the intricate interactions between stem cells, immune cells, and somatic cells that is required to rebuild and repair tissue structures. Constant inflammation runs roughshod over the delicate relationships at the heart of regeneration.
The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging.
Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo.
Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti-inflammatory therapies aiming to improve nerve regeneration in old age.