A hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia

作者：Ordonez Rueda Diana; Joensson Friederike; Mancardi David A; Zhao Weidong; Malzac Aurelie; Liang Yinming; Bertosio Elodie; Grenot Pierre; Blanquet Veronique; Sabrautzki Sybille; de Angelis Martin Hrabe; Meresse Stephane; Duprez Estelle; Bruhns Pierre; Malissen Bernard^*; Malissen Marie

来源：European Journal of Immunology, 2012, 42(9): 2395-2408.

DOI：10.1002/eji.201242589

• Bacterial infection
• Functional genomics
• Inflammation
• Mouse model
• Neutrophils

Using N-ethyl-N-nitrosourea-induced mutagenesis, we established a mouse model with a novel form of neutropenia resulting from a point mutation in the transcriptional repressor Growth Factor Independence 1 (Gfi1). These mice, called Genista, had normal viability and no weight loss, in contrast to mice expressing null alleles of the Gfi1 gene. Furthermore, the Genista mutation had a very limited impact on lymphopoiesis or on T- and B-cell function. Within the bone marrow (BM), the Genista mutation resulted in a slight increase of monopoiesis and in a block of terminal granulopoiesis. This block occurred just after the metamyelocytic stage and resulted in the generation of small numbers of atypical CD11b+Ly-6Gint neutrophils, the nuclear morphology of which resembled that of mature WT neutrophils. Unexpectedly, once released from the BM, these atypical neutrophils contributed to induce mild forms of autoantibody-induced arthritis and of immune complex-mediated lung alveolitis. They additionally failed to provide resistance to acute bacterial infection. Our study demonstrates that a hypomorphic mutation in the Gfi1 transcriptional repressor results in a novel form of neutropenia characterized by a split pattern of functional responses, reflecting the distinct thresholds required for eliciting neutrophil-mediated inflammatory and anti-infectious responses.

• 出版日期2012-9