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Science 338 (6112): 1353-1356

Copyright © 2012 by the American Association for the Advancement of Science

Acute Inflammation Initiates the Regenerative Response in the Adult Zebrafish Brain

Nikos Kyritsis1, Caghan Kizil1, Sara Zocher1, Volker Kroehne1, Jan Kaslin1,2, Dorian Freudenreich1, Anne Iltzsche1, and Michael Brand1,*

1 Deutsche Forshungsgemeinschaft–Center for Regenerative Therapies Dresden (CRTD)–Cluster of Excellence, Technische Universität Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
2 Australian Regenerative Medicine Institute (ARMI), Monash University, Wellington Road, Clayton, Victoria 3800, Australia.


Figure 1
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Fig. 1. Leukocytes infiltrate the brain rapidly after traumatic injury and sterile infection. (A and B) Immunohistochemistry (IHC) for L-plastin in unlesioned and lesioned telencephalons. (C) Quantification of the L-plastin cells in sham-operated, lesioned, and unlesioned telencephalic hemispheres in time course. (D and E) IHC for L-plastin in phosphate-buffered saline (PBS)– and zymosan A–injected brains. (F) Quantification of the L-plastin cells in PBS- and zymosan A–injected brains in time course. ns, not significant; **P < 0.01, ***P < 0.001; scale bars, 100 μm; n = 3 brains for every experiment.

 

Figure 2
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Fig. 2. Inflammation is sufficient and necessary for the initiation of reactive proliferation and reactive neurogenesis. (A and B) IHC for S100β and PCNA in PBS- or zymosan A–injected zebrafish brains. (C) Quantification of S100β/PCNA-positive cells in PBS and zymosan A–injected brains. (D and E) IHC for HuC/D and BrdU. (F) Quantification of the HuC/D/BrdU double-positive cells between PBS and zymosan A injections. (G and H) IHC for S100β and PCNA. (I) Quantification of proliferating radial glia in both lesioned and unlesioned hemispheres between Dex- and vehicle-treated animals. (J and K) IHC for HuC/D and BrdU. (L) Quantification of the newborn neurons (HuC/D/BrdU double-positive cells). *P < 0.05, **P < 0.01, ***P < 0.001; scale bars, 100 μm; n = 4 brains for every experiment.

 

Figure 3
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Fig. 3. The CysLT1–LTC4 pathway is required and sufficient for enhanced proliferation and neurogenesis. (A) cysltr1 expression is up-regulated in the lesioned hemisphere at the ventricular zone at 3 days after lesion. (B) IHC shows that CysLT1 is expressed in radial glial cells. (C and D) cysltr1 is up-regulated significantly at the ventricular zone after zymosan A injections. (E and F) IHC for S100β and PCNA. (G) Quantification of S100β/PCNA-positive cells in dimethyl sulfoxide (DMSO)– and Pranlukast-injected brains. (H and I) IHC for HuC/D and BrdU. (J) Quantification of HuC/D/BrdU-positive cells in DMSO- and Pranlukast-injected brains. (K and L) IHC for S100β and PCNA in MetOH- and LTC4-injected brains (M) LTC4 injections initiate the reactive proliferation response. (N and O) IHC for HuC/D and BrdU. (P) LTC4 injections induce reactive neurogenesis. *P < 0.05, **P < 0.01, ***P < 0.001; scale bar in (A), 200 μm; scale bar in (B), 10 μm; scale bars in (C), (D), (K), (L), (N), and (O), 100 μm; dashed circle in (A) indicates the lesion site; n = 3 brains for every experiment.

 

Figure 4
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Fig. 4. Inflammation is sufficient and necessary for inducing regeneration-specific molecular programs. (A and B) gata3 is induced at the ventricular zone 24 hours after zymosan A injections in comparison to vehicle injections. (C) Relative fold change of gata3 expression between vehicle and zymosan A injections. (D) Relative expression levels of gata3 at 3 days after lesion in immunosuppressed and control animals. (E and F) gata3 is induced significantly in the ventricular region 24 hours after LTC4 injection, in comparison to vehicle-injected brains. (G) Relative expression levels of gata3 in vehicle- and LTC4-injected brains. (H) Quantification graph indicates that gata3 expression reduces significantly after Pranlukast injection, in comparison to vehicle-injected telencephalons. *P < 0.05, **P < 0.01, ***P < 0.001; scale bars, 100 μm; n = 3 brains for every experiment).

 


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