PMID- 27206766
OWN - NLM
STAT- MEDLINE
DCOM- 20170808
LR  - 20181113
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 197
IP  - 1
DP  - 2016 Jul 1
TI  - Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis.
PG  - 303-12
LID - 10.4049/jimmunol.1502479 [doi]
AB  - Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in 
      tissue repair and fibrosis, but its cellular source and role in regeneration 
      versus fibrosis remain unclear. In this study, we hypothesize that AREG induced 
      in bone marrow-derived CD11c(+) cells is essential for pulmonary fibrosis. Thus, 
      the objectives were to evaluate the importance and role of AREG in pulmonary 
      fibrosis, identify the cellular source of AREG induction, and analyze its 
      regulation of fibroblast function and activation. The results showed that lung 
      AREG expression was significantly induced in bleomycin-induced pulmonary 
      fibrosis. AREG deficiency in knockout mice significantly diminished pulmonary 
      fibrosis. Analysis of AREG expression in major lung cell types revealed induction 
      in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion 
      of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG 
      expression and pulmonary fibrosis. Conversely, adoptive transfer of bone 
      marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated 
      pulmonary fibrosis, but not if the donor cells were made AREG deficient prior to 
      transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast 
      proliferation, activation, and myofibroblast differentiation in an AREG-dependent 
      manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, 
      which appeared to be essential for the proliferative effect. Finally, AREG 
      significantly enhanced fibroblast motility, which was associated with increased 
      expression of alpha6 integrin. These findings suggested that induced AREG 
      specifically in recruited bone marrow-derived CD11c(+) cells promoted 
      bleomycin-induced pulmonary fibrosis by activation of fibroblast telomerase 
      reverse transcriptase-dependent proliferation, motility, and indirectly, 
      myofibroblast differentiation.
CI  - Copyright (c) 2016 by The American Association of Immunologists, Inc.
FAU - Ding, Lin
AU  - Ding L
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109.
FAU - Liu, Tianju
AU  - Liu T
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109.
FAU - Wu, Zhe
AU  - Wu Z
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109.
FAU - Hu, Biao
AU  - Hu B
AUID- ORCID: 0000-0002-4691-6490
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109.
FAU - Nakashima, Taku
AU  - Nakashima T
AUID- ORCID: 0000-0002-0035-674X
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109.
FAU - Ullenbruch, Matthew
AU  - Ullenbruch M
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109.
FAU - Gonzalez De Los Santos, Francina
AU  - Gonzalez De Los Santos F
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109.
FAU - Phan, Sem H
AU  - Phan SH
AD  - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 
      48109 shphan@umich.edu.
LA  - eng
GR  - R01 HL052285/HL/NHLBI NIH HHS/United States
GR  - R01 HL112880/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20160520
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Amphiregulin)
RN  - 0 (CD11c Antigen)
RN  - 0 (Ifnar1 protein, mouse)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (STAT2 Transcription Factor)
RN  - 0 (Toll-Like Receptors)
RN  - 156986-95-7 (Receptor, Interferon alpha-beta)
SB  - IM
MH  - Amphiregulin/genetics/*metabolism
MH  - Animals
MH  - Autocrine Communication
MH  - Bone Marrow Cells/*immunology
MH  - CD11c Antigen/metabolism
MH  - Cell Differentiation
MH  - Cells, Cultured
MH  - Cross-Priming
MH  - Dendritic Cells/*immunology
MH  - Female
MH  - Lipopolysaccharides/immunology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Pulmonary Fibrosis/*immunology
MH  - Receptor, Interferon alpha-beta/genetics
MH  - STAT2 Transcription Factor/genetics/*metabolism
MH  - Toll-Like Receptors/metabolism
PMC - PMC4912903
MID - NIHMS783292
EDAT- 2016/05/22 06:00
MHDA- 2017/08/09 06:00
PMCR- 2017/07/01
CRDT- 2016/05/22 06:00
PHST- 2015/11/24 00:00 [received]
PHST- 2016/04/27 00:00 [accepted]
PHST- 2016/05/22 06:00 [entrez]
PHST- 2016/05/22 06:00 [pubmed]
PHST- 2017/08/09 06:00 [medline]
PHST- 2017/07/01 00:00 [pmc-release]
AID - jimmunol.1502479 [pii]
AID - 10.4049/jimmunol.1502479 [doi]
PST - ppublish
SO  - J Immunol. 2016 Jul 1;197(1):303-12. doi: 10.4049/jimmunol.1502479. Epub 2016 May 
      20.