Resolution, the grail for healthy ocular inflammation

Abstract

Acute inflammation is a frequent, essential and beneficial response to maintain normal tissue function. PMN are the primary effector cells of acute inflammatory responses and their timely resolution by macrophages from an injured, stressed or infected tissues are required for the successful execution of this routine tissue response. Dysregulation of this fundamental program is a major factor in the global disease burden and contributes to many ocular diseases. Counter-regulatory signals are critical to the controlled activation of innate and adaptive immune responses in the eye and recent studies have identified two circuits in the cornea, uvea and/or retina, namely 15-lipoxygenase and heme-oxygenase, which control inflammation, promote resolution of PMN and afford neuroprotection. The role of these counter-regulator and pro-resolution circuits may provide insight into ocular inflammatory diseases and opportunities to restore stressed ocular tissue to a pre-inflammatory state, namely homeostasis, rather than limiting therapeutic options to palliative inhibition of pro-inflammatory circuits.

Figure 1. Beneficial inflammation requires active resolution

Tissues experience frequent acute inflammation in response to injury, stress or infection. Recruitment of vascular PMN is initiated and amplified by carefully regulated pro-inflammatory circuits. Successful execution of acute inflammation requires phagocytosis of spent PMN by macrophages, a non-inflammatory response. Phagocytosis of PMN induces formation of anti-inflammatory mediators and differentiation to wound healing macrophages, which are essential to restore normal tissue function. Resident circuits in the cornea, uvea and retina, namely 15-LOX and/or HO produce autacoids that counter-regulate pro-inflammatory circuits, reduce PMN infiltration and activate macrophages to remove PMN. Dysregulation of this fundamental process leads to failed PMN resolution, activation of inflammatory macrophages and T-cells, setting the stage for an inflammatory disease.

Figure 2. Biosynthetic pathways for the formation of 15-LOX-derived protective eicosanoids and docosanoids in the eye

Scheme illustrating the potential cellular and multi-cellular biosynthetic routes for NPD1 (10R,17S-dihydroxy-DHA), RvD1 (7S,8R, 17S-trihydroxy-DHA) and LXA₄ (5S,6R,15S-trihydroxy-LXA₄) during an acute inflammatory response in the human eye. Interaction of the cytoprotective hemoxygenase system (HO-1) with 15-lipoxygenase (15-LOX) and regulation by the LXA₄ receptor (ALX), which is also a receptor for RvD1, are indicated. Signaling by a potential NPD-1 G-protein coupled receptor is also shown. Docosahexaenoic acid (DHA, ω-3 PUFA) metabolic pathways are shown in blue and arachidonic acid (ω-6 PUFA) pathways are shown in black. Relative expression levels of 15-LOX and 5-LOX in epithelial cells, macrophages and PMN are indicated by font size.