Parainflammation in the Ocular System: Considerations on the Underlying Mechanisms and Treatment of Dry Eye Disease

Abstract

Introduction: The transition from regulated to dysregulated parainflammation is a new concept that needs to be elucidated to clarify the pathogenesis of dry eye disease (DED). This review summarizes the recent evidence about mechanisms that could lead to dysregulated parainflammation, proposing a new hypothesis to correlate this process with the progression to chronic inflammation.

Methods: A group of European experts on DED participated in a roundtable to discuss the role of parainflammation in the most common ocular diseases with regard to DED. Starting from the roundtable contents, a narrative review was conducted through a PubMed search based on the main topics discussed, namely: parainflammation, dysfunctional parainflammation, tear film lipid and mucin alterations, and tear cortisol.

Results: Parainflammation is involved in different ocular pathologies and is characterized by the involvement of the immune system and complement factors. In DED, continuous and persistent insults are responsible for the qualitative and quantitative alteration of the lipid and mucin components of the tear film. In addition, other contributing factors have recently been described, such as the reduction of cortisol synthesis by corneal epithelial cells. This altered condition leads to excessive macrophage activity, releasing cytokines and adhesion molecules, losing tissue homeostasis, and possibly progressing to chronic inflammation.

Conclusions: Literature evidence supports the crucial role of parainflammation and its usefulness in improving the diagnosis and treatment of DED. At the same time, further investigations are necessary to better define the transition from functional to dysfunctional parainflammation, including the role of ocular surface components other than the tear film.

Keywords: Cortisol; Dry eye disease; Dysfunctional parainflammation; Lipids; Mucins; Ocular system; Parainflammation.

Fig. 1

Schematic representation depicting parainflammation as an intermediate state between homeostasis and chronic inflammation

Fig. 2

Progression of ocular para-inflammation over time. Functional para-inflammation maintains homeostasis through increased tear production, blinking rate, mucin secretion, and epithelial turnover. As compensatory mechanisms fail, dysfunctional para-inflammation leads to elevated pro-inflammatory agents, reduced mucin and tear production, and decreased cold receptor sensitivity, resulting in a progressive loss of ocular surface homeostasis