Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=30034399
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Effective Amelioration of Liver Fibrosis Through Lentiviral Vector Carrying
Toxoplasma gondii gra15(II) in Murine Model
#MMPMID30034399
Liu L
; Jin M
; Tao Q
; Yu L
; Du J
; Wang C
; Luo Q
; Xing T
; Xu Y
; Shen J
; Chu D
Front Immunol
2018[]; 9
(?): 1572
PMID30034399
show ga
Our previous investigations indicated that in vitro polarization of mouse
macrophages by Toxoplasma gondii type (II) strain dense granule protein 15 (GRA15
(II) ), one of the genotype-associated effectors of T. gondii, induced the
phenotypes of classically activated macrophage (M1). Transfusion of the cells to
mice may effectively alleviated hepatic fibrosis caused by schistosomiasis. The
purpose of the study was to identify whether liver macrophages can be in vivo
driven to M1 macrophages by lentiviral vector (LV) carrying GRA15 (II) gene
(LV-gra15 (II) ) and to explore the potential mechanism by which the LV-gra15
(II) -activated liver macrophage (LV-gra15 (II) -M) ameliorates the hepatic
fibrosis in schistosomiasis. The mice were treated with LV-gra15 (II) by
hydrodynamic injection via the tail vein followed by challenge of Schistosoma
japonicum (S. japonicum). Our experiments showed that LV-gra15 (II) was
successfully delivered to liver macrophages and GRA15(II) was persistently
expressed in the macrophages of mice for at least 2?months. Furthermore, the
LV-gra15 (II) infected macrophages were polarized to M1 macrophages in vivo.
Consequently, mice with schistosomiasis receiving LV-gra15 (II) injection
displayed a remarkable amelioration of liver granuloma formation and collagen
deposition in association with downregulated expression of transforming growth
factor-beta1, arginase 1 (Arg-1), ?-smooth muscle actin, and an increased
expression of matrix metalloproteinase 13 (MMP13). Simultaneously, no negative
effects of liver function and vitality of mice were noted. The in vitro
experiments indicated that the C-C motif chemokine ligand 2 and nitric oxide
level were elevated in LV-gra15 (II) -M cultural supernatants; hepatocyte growth
factor expression was enhanced in LV-gra15 (II) -M. In addition, LV-gra15 (II) -M
not only secreted MMP13, which greatly degraded type (I) collagen, but also
induced murine hepatic stellate cell (HSC) line (JS1) apoptosis in the co-culture
system. Taken together, we identified for the first time that LV-gra15 (II) may
in vivo drive liver macrophages to M1 macrophage phenotypes, which helps for
alteration of the liver fibrotic microenvironment with collagen dissolution, HSC
deactivation, apoptosis and hepatocyte protection. Our study gives an insight
into the use of gene delivery with parasite-derived immunomodulatory factor as a
potential immune cell activating agent to re-equilibrate the other
pathogen-induced immune response in some chronic diseases.
free
free
free
