Intravitreal TSG-6 suppresses laser-induced choroidal neovascularization by inhibiting CCR2+ monocyte recruitment

Abstract

Choroidal neovascularization (CNV) is the hallmark of wet age-related macular degeneration (AMD), one of the leading causes of blindness in the elderly. Although the pathogenesis of CNV is not clear, a number of studies show that ocular-infiltrating macrophages and inflammation play a critical role in the development of CNV. TNFα-stimulated gene/protein (TSG)-6 is a multifunctional endogenous protein that has anti-inflammatory activities partly by regulating macrophage activation. Therefore, we here investigated the therapeutic potential of TSG-6 in a rat model of CNV induced by laser photocoagulation. Time course analysis showed that the expression of VEGF and pro-inflammatory cytokines in the choroid was up-regulated early after laser injury, and gradually decreased to baseline over 14 days. An intravitreal injection of TSG-6 suppressed the expression of VEGF and pro-inflammatory cytokines including CCL2, and reduced the size of CNV. Also, the number of Iba+ and CCR2+ cells including infiltrating macrophages was markedly lower in the CNV lesion of TSG-6-treated eyes. Further analysis identified CCR2+ CD11b+ CD11c+ cells and CCR2+ CD11b-CD11c+ cells as the cell populations that were increased by laser injury and reduced by TSG-6 treatment. Together, the results demonstrate that TSG-6 inhibits inflammation and CCR2+ monocyte recruitment into the choroid, and suppresses the development of CNV.

Choroidal Neovascularization Is Inhibited in Splenic-Denervated or Splenectomized Mice with a Concomitant Decrease in Intraocular Macrophage

“…CX3CL1/CX3CR1 signaling has been demonstrated to be required for the accumulation of Ly6C lo monocytes/macrophages [ 17 , 37 ]. Taken together, our results support the idea that CCR2 deficiency does not change distribution of the nonclassical monocytes [ 9 ]. Our findings have also suggested that Ly6C hi macrophages/monocytes are associated with exacerbation of experimental CNV.…”

“…These cells have been demonstrated to be rapidly recruited to inflamed tissues, and so Ly6C hi subtype is known as “inflammatory” monocytes. Recent studies have demonstrated that inflammatory monocyte recruitment into the choroid is suppressed by TNFα-stimulated gene/protein (TSG)-6, which is a multifunctional endogenous protein, resulting in reduced CNV lesion size in a rat model of laser-induced CNV [ 9 ]. Although a previous report demonstrated that lack of CCR2/CCL2 led to spontaneous development of CNV in mice [ 10 ], later studies refuted this by demonstrating that Rd8 gene mutation, not the lack of CCR/CCL2, was the primary cause of CNV.…”

TSG-6: A multifunctional protein with anti-inflammatory and tissue-protective properties

“…CCR5-, CCR7-and CXCR4-mediated transendothelial migration [82]. In this regard, TSG-6 has already been implicated in the regulation of dendritic cells, macrophages, monocytes, and T cells [2,22,42,79,128,133,134]. Here it should be noted that while TSG-6 inhibited chemotaxis of neutrophils, albeit much more weakly than its effect on transendothelial migration [125], there was no such effect for the other chemokines investigated (i.e.…”

“…burn-induced inflammation [42], hypertrophic scaring [142] and gingival wounding [143]), eye indications (e.g. corneal allogenic transplant rejection [128], corneal wounding [127], and age-related macular degeneration [134,144]), gastroenterology (e.g. colitis [39,131] and peritonitis [78]), metabolic disease (e.g.…”

Hypertension affects the treatment of wet age‐related macular degeneration

“…Moreover, Ang II upregulates VEGFR-2, which contributes to the development of CNV by destroying the balance of antiangiogenic and angiogenic factors (Otani et al 2001;Li et al 2019). Renin-angiotensin-aldosterone system (RAAS) hyperactivity promotes an inflammatory condition as well, and inflammation causes macrophage infiltration that induces ocular CNV (Pons et al 2011;Kim et al 2015). Thus, RAAS may aggravate the progression of wAMD, which requires wAMD patients with hypertension to need more anti-VEGF treatments than those without hypertension.…”