Fig. 8: Proposed model.

Corneal desiccation in DED (or any inflammatory stimulus in other ocular surface disorders) affects corneal nerve endings and causes overactivation of TRPV1 channels in these fibers. Orthodromic TRPV1-initiated signaling serves as a danger signal to sensory neurons and leads to trigeminal ganglion neuroinflammation, which involves the activation of neuron-associated macrophages (Mφ) and adaptive immunity. The bilateral trigeminal neuroinflammation is fostered by intereye crosstalk through intercommissural neurons in the brainstem, which may facilitate the neuroinflammatory spread in the setting of unilateral corneal injury. In turn, the neuroinflammation and TRPV1-initiated activation of trigeminal sensory neurons induce antidromic signaling to the ocular surface, leading to proinflammatory neuropeptide release and the worsening of corneal dysfunction. Thus, a TRPV1-driven corneal–trigeminal neuroinflammatory circuit that promotes corneal neuropathy is established.