Abstract
While Wiskott-Aldrich syndrome protein (WASP) plays critical roles in TCR signaling as an adaptor molecule, how it transduces innate immune signals remains to be elucidated. To investigate the roles of WASP in innate immune cells, we established bone marrow-derived macrophage (BMDM) cell lines from WASP15 transgenic (Tg) mice overexpressing the WASP N-terminal region (exons 1–5). Upon LPS stimulation, WASP15 Tg BMDM cell lines produce lower levels of inflammatory cytokines, such as TNF-α, IL-6, and IL-12p40 than the wild-type BMDM cell line. In addition, the production of nitric oxide by WASP15 Tg BMDM cells in response to LPS and IFN-γ was significantly impaired. Furthermore, we uncovered that the WASP N-terminal domain associates with the Src homology (SH) 3 domain of Bruton's tyrosine kinase (Btk). Overexpression of the WASP N-terminal domain diminishes the extent of tyrosine phosphorylation of endogenous WASP in WASP15 Tg BMDM cells, possibly by interfering with the specific binding between endogenous WASP and Btk during LPS signaling. These observations strongly suggest that the interaction between WASP N-terminal domain and Btk plays important roles in the LPS signaling cascade in innate immunity.
Highlights
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, thrombocytopenia, and susceptibility to infection, and accompanied by malignant lymphoma or serious autoimmune disease in severe cases
Western blot analysis showed that the truncated WAS protein (WASP) (WASP15) was strongly expressed only in WASP15 Tg bone marrow-derived macrophage (BMDM), while endogenous WASP was equivalently expressed in BMDMs (Fig. 1B)
This study has demonstrated that BMDM cell lines established from Tg mice that overexpress the WASP N-terminal domain exhibit impaired immunological responses to LPS, such as the production of various inflammatory cytokines or nitric oxide
Summary
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, thrombocytopenia, and susceptibility to infection, and accompanied by malignant lymphoma or serious autoimmune disease in severe cases. WAS results from various types of gene mutations in WAS protein (WASP) [1]. Symptoms of WAS are consistent with cytoskeletal defects in hematopoietic cells and suggest possible roles for WASP in actinbased processes [2]. In exploration of T cells from WAS patients and WASP-deficient mice, ectopic actin polymerization was observed at the immunological synapse after TCR ligation and resulted in impairment of IL-2 production upon TCR stimulation [3,4]. WASP is involved in the cytoskeletal rearrangement of innate immune cells. WASP-deficient monocytes and macrophages showed poor formation of the actin-rich phagocytic cup [5], and developed defects in polarization and migration in response to inflammatory chemokines in vitro [6,7]
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