Abstract
There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.
| Original language | English |
|---|---|
| Pages (from-to) | 270-277 |
| Number of pages | 8 |
| Journal | Cell Death and Differentiation |
| Volume | 21 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2014 |
| Externally published | Yes |
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Keywords
- degeneration
- macula
- necrosis
- neuroprotection
- retina
ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
- Medicine(all)
Cite this
Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. / Murakami, Y.; Matsumoto, H.; Roh, M.; Giani, A.; Kataoka, K.; Morizane, Yuki; Kayama, M.; Thanos, A.; Nakatake, S.; Notomi, S.; Hisatomi, T.; Ikeda, Y.; Ishibashi, T.; Connor, K. M.; Miller, J. W.; Vavvas, D. G.
In: Cell Death and Differentiation, Vol. 21, No. 2, 02.2014, p. 270-277.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration
AU - Murakami, Y.
AU - Matsumoto, H.
AU - Roh, M.
AU - Giani, A.
AU - Kataoka, K.
AU - Morizane, Yuki
AU - Kayama, M.
AU - Thanos, A.
AU - Nakatake, S.
AU - Notomi, S.
AU - Hisatomi, T.
AU - Ikeda, Y.
AU - Ishibashi, T.
AU - Connor, K. M.
AU - Miller, J. W.
AU - Vavvas, D. G.
PY - 2014/2
Y1 - 2014/2
N2 - There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.
AB - There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD.
KW - degeneration
KW - macula
KW - necrosis
KW - neuroprotection
KW - retina
UR - http://www.scopus.com/inward/record.url?scp=84892439582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892439582&partnerID=8YFLogxK
U2 - 10.1038/cdd.2013.109
DO - 10.1038/cdd.2013.109
M3 - Article
C2 - 23954861
AN - SCOPUS:84892439582
VL - 21
SP - 270
EP - 277
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 2
ER -