Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia

Abstract

A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Aip1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow-derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types.

Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β

“…To establish whether the pathogenic IL-18 observed in these animals derives from hematopoietic cells, we generated BM chimeras by transplanting unfractionated BM cells into lethally irradiated recipients. Consistent with our previous study (Kile et al, 2007), transfer of Wdr1 rd/rd BM into wild-type recipients triggered autoinflammatory disease a median of 22 d after of inflammation in this genetic condition are unclear (Kile et al, 2007). Intriguingly, Wdr1 was found to be secreted after caspase-1 activation (Keller et al, 2008).…”

“…It was previously shown that the rd allele of Wdr1 is hypomorphic and not a complete loss of function, whereas Wdr1 deficiency caused by a gene-trap allele (Wdr1 xn/xn ) causes embryonic lethality because of developmental abnormalities (Kile et al, 2007). The compound heterozygote (Wdr1 xn/rd ) exhibits an intermediate phenotype, and mice die at birth from an unknown etiology (unpublished data).…”

“…In addition to the massive infiltration of neutrophils, F4/80 + macrophages were found in the inflammatory lesions of the Wdr1 rd/rd ears (Kile et al, 2007). To study inflammasome function in macrophages, we derived macrophages in M-CSF for 7 d-the standard technique for generation of macrophages cells was consistent with monocytes and not mature macrophages (Fig.…”

“…Mice homozygous for a hypomorphic allele of Wdr1 (Wdr1 rd/rd ) exhibit spontaneous autoinflammatory disease and thrombocytopenia (Kile et al, 2007). Both defects have been suggested to result from a disruption in actin dynamics.…”

“…IL-18 from the hematopoietic compartment contributes to disease in Wdr1 rd/rd mice We previously reported that the autoinflammatory disease in Wdr1 rd/rd mice is BM intrinsic (Kile et al, 2007). To establish whether the pathogenic IL-18 observed in these animals derives from hematopoietic cells, we generated BM chimeras by transplanting unfractionated BM cells into lethally irradiated recipients.…”