The Subtle Role of Para-inflammation in Modulating the Progression of Dry Eye Disease

In patients with DED, the continuous stimuli induced by excessive or persistent cold fiber sensors and overstimulation of nociceptors, as well as tear hyperosmolarity induced by evaporative stress, induce a transitory protective adaptation response called para-inflammation to restore ocular surface homeostasis. This mild subclinical inflammatory status (a type of hormetic response) can become chronic if the stimuli or tissue malfunction is present for a sustained period, causing persistent symptoms and damage to ocular surface epithelia. We review the mechanisms that characterize the transition from para-inflammation to a persistent inflammatory status of the ocular surface, including accumulation of biological waste and damaged/dysfunctional proteins, which, in normal conditions, are eliminated by autophagy, activation of the inflammasomes, and what is currently known about their role in DED pathogenesis. Furthermore, we analyze current treatments that can modulate the inflammatory response of the ocular surface and speculate about new possible therapies to treat para-inflammation.