Necroptosis and Neuroinflammation in Retinal Degeneration

Abstract

Necroptosis mediates the chronic inflammatory phenotype in neurodegeneration. Receptor-interacting protein kinase (RIPK) plays a pivotal role in the induction of necroptosis in various cell types, including microglia, and it is implicated in diverse neurodegenerative diseases in the central nervous system and the retina. Targeting RIPK has been proven beneficial for alleviating both neuroinflammation and degeneration in basic/preclinical studies. In this review, we discuss the role of necroptosis in retinal degeneration, including (1) the molecular pathways involving RIPK, (2) RIPK-dependent microglial activation and necroptosis, and (3) the interactions between necroptosis and retinal neuroinflammation/degeneration. This review will contribute to a renewed focus on neuroinflammation induced by necroptosis and to the development of anti-RIPK drugs against retinal degeneration.

Keywords: RIPK; microglia; necroptosis; neuroinflammation; retinal degeneration.

Figure 1

Structure of RIPK1, RIPK3 and MLKL. KD, N-terminal kinase domain; ID, intermediate domain; RHIM, RIP homotypic interaction motif; DD, death domain; 4HB, 4-helix bundle; PsKD, pseudokinase domain.

Figure 2

RIPK signaling. TNFR1 recruits RIPK1, TRADD, TRAF2, and cIAP1/2. cIAP1/2 initiates the ubiquitination process on complex I. The K63 Ub chain of RIPK1 links molecules in the large TNF complex I. The TAK1 complex phosphorylates IKKβ to induce NF-κB activation. When NF-κB, the complex of cIAP1/2, or LUBAC, TAK1, or TBK1 is inhibited, membrane-bound complex I is dissociated and complex II is formed. If NF-κB is inhibited, TRADD, FADD and caspase-8 form complex IIa, inducing RIPK1-independent apoptosis. When inhibition of cIAP1/2, TAK1, TBK1, or LUBAC occurs, RIPK1, FADD, caspase-8, and c-FLIPL form complex IIb, inducing RIPK1-dependent apoptosis. Procaspase-8/cFLIPL heterodimers prevent necroptosis. Upon caspase-8 inhibition, complex IIb initiates RIPK1- and RIPK3-dependent necroptosis. Activated RIPK1 heterodimerizes with RIPK3 and RIPK3 phosphorylates MLKL, thereby driving the polymerization of RIPK1, RIPK3 and MLKL. This RIPK1-RIPK3-MLKL complex is called a “necrosome.” In macrophages/microglia, LPS or poly(I:C) is recognized by TLR4 and mediates the interaction between TRIF and RIPK3. In the presence of caspase inhibitor, the TRIF/RIPK3 complex induces ROS accumulation, and subsequently triggers necroptosis independent of NF-κB activation. TLR4 also recruits MyD88 and cIAPs to activate the NF-κB pathway, thereby inducing pro-inflammatory cytokines. TNF-α, tumor necrosis factor-α; TNFR1, TNFα receptor 1; RIPK1/3, receptor-interacting protein kinases 1/3; TRADD, TNFR1-associated death domain protein; TRAF2, TNF receptor associated factor 2; cIAP1/2, cellular inhibitor of apoptosis 1/2; HOIL-1, haem-oxidized iron-regulatory protein 2 ubiquitin ligase-1; HOIP, HOIL-1 interacting protein; SHARPIN, SHANK-associated RH domain-interacting protein; NF-κB, nuclear factor-κB; NEMO, cell death-protective nuclear factor-κB essential modulator; IKKα/β, inhibitor of NF-κB kinase α/β; TAB2/3, TAK1-binding protein 2 and 3; FADD, Fas associated via death domain; cFLIP_L, the long isoform of cellular FLICE-like inhibitory protein; MLKL, mixed lineage kinase domain-like protein; TIRF, TIR-domain containing adapter-inducing interferon-b; MYD88, myeloid differentiation primary response gene 88; SMs, SMAC mimetics; ROS, reactive oxygen species.

Figure 3

Microglia/Macrophages in retinal disorders. Schematic representation of necroptotic and activated microglia/macrophages in retinal necroptosis and inflammation. Various damages and DAMPs activate innate immune cells. Activated and necroptotic microglia/macrophages via inflammasome-dependent/-independent mechanisms secrete inflammatory and angiogenic mediators. These pro-inflammatory and angiogenic factors induce choroidal neovascularization. Pro-inflammatory factors and DAMPs also lead to necrotic cell death of RGCs, RPE cells and photoreceptors. Moreover, activated microglia/macrophages infiltrate to the outer retina to phagocytose dead cells and modulate inflammation.