Retinal Laser Burn-Induced Neuropathy Leads to Substance P-Dependent Loss of Ocular Immune Privilege

Abstract

Inflammation in the eye is tightly regulated by multiple mechanisms that together contribute to ocular immune privilege. Many studies have shown that it is very difficult to abrogate the immune privileged mechanism called anterior chamber associated immune deviation (ACAID). Previously, we showed that retinal laser burn (RLB) to one eye abrogated immune privilege (ACAID) bilaterally for an extended period of time. In an effort to explain the inflammation in the non-burned eye, we postulated that neuronal signals initiated inflammation in the contralateral eye. Here, we test the role of substance P, a neuroinflamatory peptide, in RLB-induced loss of ACAID. Histological examination of the retina with and without RLB revealed an increase of the substance P-inducible neurokinin 1 receptor (NK1-R) in the retina of first, the burned eye, and then the contralateral eye. Specific antagonists for NK1-R, given locally with antigen within 24h, but not 3,5, or 7 days post RLB treatment, prevented the bilateral loss of ACAID. Substance P Knockout (KO) mice retained their ability to develop ACAID post RLB. These data support the postulate that substance P transmits early inflammatory signals from the RLB eye to the contralateral eye to induce changes to ocular immune privilege and has a central role in the bilateral loss of ACAID. The possibility is raised that blocking of the substance P pathway with NK1-R antagonists post ocular trauma may prevent unwanted and perhaps extended consequences of trauma-induced inflammation in the eye.

Effect of Corneal Nerve Ablation on Immune Tolerance Induced by Corneal Allografts, Oral Immunization, or Anterior Chamber Injection of Antigens

“…11 Interestingly, laser burns to the retina induce an upregulation in NK1-R, the receptor for SP, which is associated with the abrogation of ACAID. 26,27 Accordingly, we examined the eyes of mice following trephining for the upregulation NK1-R message in trephined eyes and the contralateral nonmanipulated eyes of BALB/c mice. The results revealed a spike in NK1-R message 14 days following trephining and a return to baseline levels by day 21 (Fig.…”

“…28 Similarly, laser burns to the retina elicit a 10-fold increase in the expression of NK1-R in the opposite eye and prevent the induction of ACAID in both eyes. 26 With this in mind, we examined the effect of trephining, SP, and orthotopic corneal transplantation on the induction of ACAID in both eyes.…”

“…These findings are reminiscent of a previous report indicating that retinal laser burns (RLB) to one eye evoked a sharp increase in NK1-R expression in both the manipulated and the contralateral nonmanipulated eye. 26 Importantly, RLB prevented the induction of ACAID in either the burned eye or the nonmanipulated eye and persisted for at least 68 days. 26 The present findings indicate that trephining the corneal surface leads to a transient ablation of corneal nerves, which return to their normal density within 4 days.…”

Macro- and microglial responses in the fellow eyes contralateral to glaucomatous eyes

“…It has been postulated that ACAID is difficult to abrogate; however, it has been recently reported that unilateral injury to one eye such as retinal laser burn (Qiao et al, 2009), ON crush or trauma in different regions of the optic pathway (Stein-Streilein, 2012), abrogate ACAID bilaterally for an extended time period. Lucas et al (2012) suggested that the substance P (an inflammatory neuropeptide) acts in the neurologic communication between the two eyes and is involved in the loss of immune regulation post-ocular trauma. It is now well accepted that neurogenic mechanisms contribute to the symmetrical spread of inflammation in rheumatoid arthritis (Donaldson et al, 1995;Kelly et al, 2007) and that transneuronal signaling between damaged neurons and their contralateral homologues prevent the spread of peripheral nerve damage (Kolston et al, 1991).…”

Neuropeptide substance P and the immune response

“…Amacrine-derived SP has been reported to be involved in the loss of immune privilege post retinal laser burn through its potential to promote an inflammatory environment that in turn activates resident macrophages and microglia. NK1R antagonists could prevent or curb inflammation post ocular trauma (Lucas et al, 2012). On the other hand, there are reports on anti-inflammatory effects of SP in the retina.…”