Increased Fanconi C expression contributes to the emergency granulopoiesis response
Liping Hu, … , Elizabeth Hjort, Elizabeth A. Eklund
Liping Hu, … , Elizabeth Hjort, Elizabeth A. Eklund
Published August 8, 2013
Citation Information: J Clin Invest. 2013;123(9):3952-3966. https://doi.org/10.1172/JCI69032.
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Research Article Hematology

Increased Fanconi C expression contributes to the emergency granulopoiesis response

Abstract

Emergency granulopoiesis is a component of the innate immune response that is induced in response to infectious or inflammatory challenge. It is characterized by the rapid expansion and differentiation of granulocyte/monocyte progenitor (GMP) populations, which is due in part to a shortened S-phase of the cell cycle. We found that IRF8 (also known as ICSBP), an interferon regulatory transcription factor that activates phagocyte effector genes during the innate immune response, activates the gene encoding Fanconi C (Fancc) in murine myeloid progenitor cells. Moreover, IRF8-induced Fancc transcription was augmented by treatment with IL-1β, an essential cytokine for emergency granulopoiesis. The Fanconi pathway participates in repair of stalled or collapsed replication forks during DNA replication, leading us to hypothesize that the Fanconi pathway contributes to genomic stability during emergency granulopoiesis. In support of this hypothesis, Fancc–/– mice developed anemia and neutropenia during repeated, failed episodes of emergency granulopoiesis. Failed emergency granulopoiesis in Fancc–/– mice was associated with excess apoptosis of HSCs and progenitor cells in the bone marrow and impaired HSC function. These studies have implications for understanding the pathogenesis of bone marrow failure in Fanconi anemia and suggest possible therapeutic approaches.

Authors

Liping Hu, Weiqi Huang, Elizabeth Hjort, Elizabeth A. Eklund

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Figure 5

FANCC-deficient mice exhibit an abnormal emergency granulopoiesis response.

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FANCC-deficient mice exhibit an abnormal emergency granulopoiesis respon...
(A) Fancc+/– and Fancc–/– mice fail to exhibit granulocytosis upon Alum injection. WT, Fancc+/–, and Fancc–/– mice were injected with saline or Alum in the peritoneal cavity every 4 weeks. Some mice were pretreated with IL-1R antagonist (anakinra [Kineret]) 24 hours prior to and following Alum injection. Peripheral blood granulocyte counts were determined every 2 weeks. Statistically significant differences that developed over time are indicated by *P < 0.01, **P < 0.01, or ***P < 0.01. (B) FANCC-deficient mice exhibit progressive anemia with repeated Alum injection. Mice described above were also evaluated for Hgb concentration every 2 weeks. Statistically significant differences that developed over time are indicated by *P < 0.01 and **P < 0.01. (C) IL-1β and G-CSF production are similar in Alum-injected WT and Fancc–/– mice. Serum levels of IL-1β and G-CSF were determined in WT or Fancc–/– mice injected with Alum or saline. Statistically significant differences with versus without Alum are indicated by *P < 0.01, **P < 0.01, #P < 0.01, or ##P < 0.01. (D) Lymphopenia occurs in WT and Fancc–/– mice after Alum injection. The percentage decrease in lymphocyte counts after Alum injection were determined in WT and Fancc–/– mice, with versus without anakinra pretreatment. Lymphocyte counts were not altered by saline injection (data not shown). EG, emergency granulopoiesis.