TREM2 deficiency in microglia accelerates photoreceptor cell death and immune cell infiltration following retinal detachment

Abstract

Retinal detachment (RD) occurs in several major retinal conditions and often causes irreversible vision loss due to photoreceptor cell death. Retinal residential microglial cells are activated following RD and participate in photoreceptor cell death via direct phagocytosis and the regulation of inflammatory responses. Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor exclusively expressed on microglial cells in the retina, and has been reported to affect microglial cell homeostasis, phagocytosis and inflammatory responses in the brain. In this study, increased expression of multiple cytokines and chemokines in the neural retina was observed starting at 3 h following RD. Trem2 knockout (Trem2−/−) mice exhibited significantly more photoreceptor cell death than wild-type controls at 3 days after RD, and the number of TUNEL positive photoreceptor cells progressively decreased from day 3 to day 7 post-RD. A significant thinning of the outer nuclear layer (ONL), with multiple folds was observed in the Trem2−/− mice at 3 days post-RD. Trem2 deficiency reduced microglial cell infiltration and phagocytosis of stressed photoreceptors. There were more neutrophils in Trem2−/− retina following RD than in controls. Using purified microglial cells, we found Trem2 knockout is associated with increased CXCL12 expression. The aggravated photoreceptor cell death was largely reversed by blocking the CXCL12-CXCR4 mediated chemotaxis in Trem2−/− mice after RD. Our findings suggested that retinal microglia are protective in preventing further photoreceptor cell death following RD by phagocytosing presumably stressed photoreceptor cells and by regulating inflammatory responses. TREM2 is largely responsible for such protective effect and CXCL12 plays an important role in regulating neutrophil infiltration after RD. Collectively, our study pinpointed TREM2 as a potential target of microglial cells to ameliorate RD-induced photoreceptor cell death.

Serum amyloid A aggravates endotoxin‐induced ocular inflammation through the regulation of retinal microglial activation

“…Evidence supporting the role of SAA in mitigating inflammatory responses also came from other studies. In fact, our previous studies showed that Saa3 was among the top upregulated genes in mouse model of retinal detachment and retinal degeneration 26 . It was shown that SAA regulates IL‐17 production 36,37 .…”

“…In fact, our previous studies showed that Saa3 was among the top upregulated genes in mouse model of retinal detachment and retinal degeneration. 26 It was shown that SAA regulates IL-17 production. 36,37 Further study demonstrated that SAA directly regulates Th17 cell differentiation.…”

“…Immunohistochemistry analysis of frozen tissue sections was conducted as previously described. 26 The eyecup without lens was fixed in freshly prepared 4% paraformaldehyde (PFA) for 1 h at room temperature, sequentially dehydrated in 20% and 40% sucrose at 4°C, embedded in optimal cutting temperature compound (OCT), and sectioned at 10 μm thickness using a microtome (HM525 NX, Thermo Fisher Scientific). Tissue sections were blocked with 10% goat serum and permeabilized with 0.2% Triton X-100 for 2 h at room temperature, and incubated with primary antibodies overnight at 4°C.…”