A Hypothalamic-Controlled Neural Reflex Promotes Corneal Inflammation

Abstract

Purpose To test whether an acute corneal injury activates a proinflammatory reflex, involving corneal sensory nerves expressing substance P (SP), the hypothalamus, and the sympathetic nervous system. Methods C57BL6/N (wild-type [WT]) and SP-depleted B6.Cg-Tac1tm1Bbm/J (TAC1-KO) mice underwent bilateral corneal alkali burn. One group of WT mice received oxybuprocaine before alkali burn. One hour later, hypothalamic neuronal activity was assessed in vivo by magnetic resonance imaging and ex vivo by cFOS staining. Some animals were followed up for 14 days to evaluate corneal transparency and inflammation. Tyrosine hydroxylase (TH), neurokinin 1 receptor (NK1R), and neuronal nitric oxide synthase (nNOS) expression was assessed in brain sections. Sympathetic neuron activation was evaluated in the superior cervical ganglion (SCG). CD45 + leukocytes were quantified in whole-mounted corneas. Noradrenaline (NA) was evaluated in the cornea and bone marrow. Results Alkali burn acutely induced neuronal activation in the trigeminal ganglion, paraventricular hypothalamus, and lateral hypothalamic area (PVH and LHA), which was significantly lower in TAC1-KO mice ( P < 0.05). Oxybuprocaine application similarly reduced neuronal activation ( P < 0.05). TAC1-KO mice showed a reduced number of cFOS + /NK1R + /TH + presympathetic neurons ( P < 0.05) paralleled by higher nNOS expression ( P < 0.05) in both PVH and LHA. A decrease in activated sympathetic neurons in the SCG and NA levels in both cornea/bone marrow and reduced corneal leukocyte infiltration ( P < 0.05) in TAC1-KO mice were found. Finally, 14 days after injury, TAC1-KO mice showed reduced corneal opacity and inflammation ( P < 0.05). Conclusions Our findings suggest that stimulation of corneal sensory nerves containing SP activates presympathetic neurons located in the PVH and LHA, leading to sympathetic activation, peripheral release of NA, and corneal inflammation.

Neuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation

“…In animal models of bacterial keratitis (Pseudomonas aeruginosa), SP causes an elevation of levels of pro-inflammatory cytokines (Foldenauer et al, 2012;McClellan et al, 2008), and application of a SP antagonist improves disease outcomes (Hazlett et al, 2007). Excessive release of SP may further promote leukocyte infiltration and delay the apoptosis of neutrophils, leading to neurogenic inflammation (Lasagni Vitar et al, 2022;Zhou et al, 2008). In addition, SP is also reported to promote inflammatory corneal neovascularisation, with increased infiltration of CD45 + leukocytes in mouse corneas after total de-epithelisation, alkali burn, or intrastromal sutures (Barbariga et al, 2018).…”

“…Neurogenic inflammation in the cornea provides evidence for corneal neuroimmune crosstalk. Corneal nerve damage induces immune responses to promote the clearance of disrupted axons, and release of neurotrophic factors that trigger inflammation (Lasagni Vitar et al, 2022). The inflammatory response, including activation of immune cells and released cytokines, can further induce nerve damage, to propogate the corneal neuroinflammation (Launay et al, 2016).…”

Aprepitant Restores Corneal Sensitivity and Reduces Pain in DED

“… 25 More recently, we also showed that following chemical damage of the ocular surface, mice that are genetically unable to express SP showed reduced lymphocyte infiltration and inflammatory response compared to wild-type mice. 58 Finally, we previously observed that topical administration of NK1R antagonist fosaprepitant reduced corneal epithelial disease and inflammation in a murine model of graft-versus-host disease. 59 Others have reported the analgesic potential of NK1 receptor antagonist administration in murine models of acute pancreatitis, 60 interstitial cystitis, 61 and chronic pain.…”

Dopamine Receptor 1 Treatment Promotes Epithelial Repair of Corneal Injury by Inhibiting NOD-Like Receptor Protein 3–Associated Inflammation

“…Recent investigations have revealed that nerve reflexes, orchestrated by the hypothalamus, contribute to corneal inflammation. 23 DRD1, being a prevalent neuroreceptor, likely plays a role in the inflammatory feedback loop within the central axis in the context of corneal injury. Delving into these intricate mechanisms holds promise for future explorations within the realm of corneal injury research.…”