Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation

Abstract

Inflammation has emerged to be a critical mechanism responsible for neural damage and neurodegenerative diseases. Microglia, the resident innate immune cells in retina, are implicated as principal components of the immunological insult to retinal neural cells. The involvement of microglia in retinal inflammation is complex and here we propose for the first time that necroptosis in microglia triggers neuroinflammation and exacerbates retinal neural damage and degeneration. We found microglia experienced receptor-interacting protein kinase 1 (RIP1)- and RIP3-dependent necroptosis not only in the retinal degenerative rd1 mice, but also in the acute retinal neural injury mice. The necroptotic microglia released various pro-inflammatory cytokines and chemokines, such as tumor necrosis factor-α and chemokine (C-C motif) ligand 2, which orchestrated the retinal inflammation. Importantly, necroptosis blockade using necrostatin-1 could suppress microglia-mediated inflammation, rescue retinal degeneration or prevent neural injury in vivo. Meanwhile, cultured microglia underwent RIP1/3-mediated necroptosis and the necroptotic microglia produced large amounts of pro-inflammatory cytokines in response to lipopolysaccharide or oxidative stress in vitro. Mechanically, TLR4 deficiency ameliorated microglia necroptosis with decreased expression levels of machinery molecules RIP1 and RIP3, and suppressed retinal inflammation, suggesting that TLR4 signaling was required in microglia necroptosis-mediated inflammation. Thus, we proposed that microglia experienced necroptosis through TLR4 activation, promoting an inflammatory response that serves to exacerbate considerable neural damage and degeneration. Necroptosis blockade therefore emerged as a novel therapeutic strategy for tempering microglia-mediated neuroinflammation and ameliorating neural injury and neurodegenerative diseases.

Large-scale Phenotypic Drug Screen Identifies Neuroprotectants in Zebrafish and Mouse Models of Retinitis Pigmentosa

“…As noted above, we found that inhibiting necroptosis but not apoptosis promoted rod cell survival in fish (Figure 4 and Table 2). Necroptosis is primarily associated with secondary cone cell death in RP models (Murakami et al, 2015(Murakami et al, , 2012Yang et al, 2017) but has also been implicated in rod cell death in IRBP mutant RP models (Sato et al, 2013) and/or may damage photoreceptors indirectly via necroptotic microglia signaling (Huang et al, 2018). Combined, these results suggest that necroptosis, PARP1-dependent parthanatos, and/or c-GMP-dependent cell death mediate NTR/Mtz-induced rod cell ablation.…”

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…In the mouse retina, pre‐diabetic conditions and high‐fat diet caused TLR4‐dependent activation of microglia ad macrophages concomitant with vision loss (Lee et al, ). Microglia themselves can experience necroptosis, a form of inflammatory cell death, through TLR4 activation in rd 1 mice, thereby exacerbating retinal inflammation and damage (Huang et al, ).…”

Peripheral inflammation promotes brain tau transmission via disrupting blood–brain barrier

“…Toll-like receptor 4 (TLR4), a member of the Toll-like receptor family, is a transmembrane protein encoded by the TLR4 gene. TLR4 belonging to the pattern recognition receptor (PRR) family is the most important receptor for LPS-activated microglia [28][29][30][31]. Depletion of microglia halted tau transmission in AD mouse model [8].…”