Surprisingly, we found that proinflammatory cytokines were increased not only in the TG homolateral to the injury, but also in the contralateral one, although no significant inflammatory cell infiltration was detected in the latter. In this regard, there is increasing evidence that unilateral nerve injury evokes contralateral responses, but the underlying mechanisms are largely unknown. The bilateral effects after unilateral nerve damage have recently been reported in a mouse model of neurotrophic keratopathy.
42 Yamaguchi et al.
42 observed some corneal epithelial defects followed by corneal neovascularization and a sub-basal corneal nerve reduction in the untreated contralateral eyes. Bilateral nerve alteration has been also found in patients with unilateral herpes simplex keratitis
43 and herpes zoster ophthalmicus.
44 These midline-crossing effects were also previously documented in contralateral undamaged neurons after peripheral nerve lesions.
45,46 Interestingly, the release of inflammatory mediators from neurons, such as TNF-α, IL-1β, Substance P, and others, has been suggested to mediate these bilateral effects.
45–47 Intriguingly, we found these inflammatory mediators increased also in the TG. Corneal innervation is generally considered to travel along a unilateral nerve pathway
48 ; however, impairment of contralateral nerve function has been noticed in monocular herpetic keratitis.
49 This was further confirmed by others
44 and is likely mediated by corneal nerves, although the precise mechanism is still unclear. Projections of trigeminal neurons innervating bilateral brainstem areas and crossing between trigeminal nuclei of both sides have been observed,
50,51 suggesting anatomical structures involved in these midline-crossing effects. Additionally, it has been proposed that Substance P may mediate loss of immune privilege to the contralateral eye following a retinal laser burn.
35 For this reason, we used healthy animals as controls. Finally, contralateral involvement induced by Substance P and other neuropeptides has also been described in monoarthritis.
52