Figure 1.

Proposed adaptive mechanism of neural plasticity from STs innervating secondary lymphoid organs such as the spleen. The activation of the IS may be accompanied by retraction and axonal degeneration of STs (red arrows). The activated immune cells are able to produce semaphorins and pro-neurotrophins/neurotrophins, binding to their receptors -plexins/neuropilins and Trk/p75NTR, respectively- probably expressed on STs. In particular, p75NTR may be re-expressed in a pro-inflammatory milieu. The action of these molecules may lead to an inhibition of STs integrin-mediated adhesion to ECM and depolymerization of their actin cytoskeleton, thus favoring their retraction and axonal degeneration (dotted line). In addition, semaphorins and neurotrophins/pro-neurotrophins may be produced by other non-lymphoid cell types as well (i.e., stromal cells), under cytokine influence. A direct action of cytokines as playing a role on STs retraction cannot be disregarded. Once the immune response ceases, the IS returns to the steady state and STs may regenerate, recovering the usual splenic innervation pattern (blue arrows). Neural and immunological phenomena are summarized on the left and right sides, respectively. STs, sympathetic terminals; IS, immune system; Trk, tropomyosin-related kinase; p75NTR, p75 neurotrophin receptor; ECM, extracellular matrix.