Neutropenia with impaired host defense against microbial infection in mice lacking androgen receptor.
Neutrophils, the major phagocytes that form the first line of cell-mediated defense against microbial infection, are produced in the bone marrow and released into the circulation in response to granulocyte-colony stimulating factor (G-CSF). Here, we report that androgen receptor knockout (ARKO) mice are neutropenic and susceptible to acute bacterial infection, whereas castration only results in moderate neutrophil reduction in mice and humans. Androgen supplement can restore neutrophil counts via stabilizing AR in castrated mice, but not in ARKO and testicular feminization mutant (Tfm) mice. Our results show that deletion of the AR gene does not influence myeloid lineage commitment, but significantly reduces the proliferative activity of neutrophil precursors and retards neutrophil maturation. CXCR2-dependent migration is also decreased in ARKO neutrophils as compared with wild-type controls. G-CSF is unable to delay apoptosis in ARKO neutrophils, and ARKO mice show a poor granulopoietic response to exogenous G-CSF injection. In addition, AR can restore G-CSF-dependent granulocytic differentiation upon transduction into ARKO progenitors. We further found that AR augments G-CSF signaling by activating extracellular signal-regulated kinase 1/2 and also by sustaining Stat3 activity via diminishing the inhibitory binding of PIAS3 to Stat3. Collectively, our findings demonstrate an essential role for AR in granulopoiesis and host defense against microbial infection.
George Whipple Laboratory for Cancer Research, Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Kuang-Hsiang
KH
Chuang
Saleh
S
Altuwaijri
Gonghui
G
Li
Jiann-Jyh
JJ
Lai
Chin-Yi
CY
Chu
Kuo-Pao
KP
Lai
Hung-Yun
HY
Lin
Jong-Wei
JW
Hsu
Peter
P
Keng
Ming-Chi
MC
Wu
Chawnshang
C
Chang
D000818:Animals; D001424:Bacterial Infections / Q000235:genetics* / Q000517:prevention & control; D002454:Cell Differentiation; D017931:DNA Primers; D006098:Granulocytes / Q000166:cytology / Q000382:microbiology / Q000502:physiology; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009503:Neutropenia / Q000209:etiology* / Q000382:microbiology*; D011944:Receptors, Androgen / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic
D017931:DNA Primers; D011944:Receptors, Androgen