PMID- 33057437
OWN - NLM
STAT- MEDLINE
DCOM- 20201209
LR  - 20201214
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 15
IP  - 10
DP  - 2020
TI  - Characterization of hepatic macrophages and evaluation of inflammatory response 
      in heme oxygenase-1 deficient mice exposed to scAAV9 vectors.
PG  - e0240691
LID - 10.1371/journal.pone.0240691 [doi]
LID - e0240691
AB  - Adeno-associated viral (AAV) vectors are characterised by low immunogenicity, 
      although humoral and cellular responses may be triggered upon infection. 
      Following systemic administration high levels of vector particles accumulate 
      within the liver. Kupffer cells (KCs) are liver resident macrophages and an 
      important part of the liver innate immune system. Decreased functional activity 
      of KCs can contribute to exaggerated inflammatory response upon antigen exposure. 
      Heme oxygenase-1 (HO-1) deficiency is associated with considerably reduced 
      numbers of KCs. In this study we aimed to investigate the inflammatory responses 
      in liver and to characterise two populations of hepatic macrophages in adult wild 
      type (WT) and HO-1 knockout (KO) mice following systemic administration of one or 
      two doses (separated by 3 months) of self-complementary (sc)AAV9 vectors. At 
      steady state, the livers of HO-1 KO mice contained significantly higher numbers 
      of monocyte-derived macrophages (MDMs), but significantly less KCs than their WT 
      littermates. Three days after re-administration of scAAV9 we observed increased 
      mRNA level of monocyte chemoattractant protein-1 (Mcp-1) in the livers of both WT 
      and HO-1 KO mice, but the protein level and the macrophage infiltration were not 
      affected. Three days after the 1st and 3 days after the 2nd vector dose the 
      numbers of AAV genomes in the liver were comparable between both genotypes 
      indicating similar transduction efficiency, but the percentage of 
      transgene-expressing MDMs and KCs was higher in WT than in HO-1 KO mice. In the 
      primary culture, KCs were able to internalize AAV9 particles without induction of 
      TLR9-mediated immune responses, but no transgene expression was observed. In 
      conclusion, in vivo and in vitro cultured KCs have different susceptibility to 
      scAAV9 vectors. Regardless of the presence or absence of HO-1 and initial numbers 
      of KCs in the liver, scAAV9 exhibits a low potential to stimulate inflammatory 
      response at the analysed time points.
FAU - Tomczyk, Mateusz
AU  - Tomczyk M
AD  - Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Kraszewska, Izabela
AU  - Kraszewska I
AD  - Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Maka, Robert
AU  - Maka R
AD  - Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Waligorska, Agnieszka
AU  - Waligorska A
AD  - Department of Cell Biophysics, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Dulak, Jozef
AU  - Dulak J
AD  - Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Jazwa-Kusior, Agnieszka
AU  - Jazwa-Kusior A
AUID- ORCID: 0000-0001-9107-4395
AD  - Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201015
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Chemokine CCL2)
RN  - 0 (Interleukin-6)
RN  - 0 (Toll-Like Receptor 9)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
SB  - IM
MH  - Animals
MH  - Cells, Cultured
MH  - Chemokine CCL2/metabolism
MH  - Dependovirus/metabolism
MH  - Gene Expression Regulation
MH  - Genetic Vectors/*metabolism
MH  - Green Fluorescent Proteins/metabolism
MH  - HEK293 Cells
MH  - Heme Oxygenase-1/*deficiency/metabolism
MH  - Humans
MH  - Inflammation/blood/genetics/*pathology
MH  - Interleukin-6/blood
MH  - Kupffer Cells/pathology
MH  - Liver/*pathology
MH  - Macrophages/*pathology
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Phenotype
MH  - Signal Transduction/genetics
MH  - Toll-Like Receptor 9/metabolism
MH  - Transgenes
PMC - PMC7561190
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/10/16 06:00
MHDA- 2020/12/15 06:00
PMCR- 2020/10/15
CRDT- 2020/10/15 17:33
PHST- 2020/05/03 00:00 [received]
PHST- 2020/09/30 00:00 [accepted]
PHST- 2020/10/15 17:33 [entrez]
PHST- 2020/10/16 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/10/15 00:00 [pmc-release]
AID - PONE-D-20-13005 [pii]
AID - 10.1371/journal.pone.0240691 [doi]
PST - epublish
SO  - PLoS One. 2020 Oct 15;15(10):e0240691. doi: 10.1371/journal.pone.0240691. 
      eCollection 2020.