Mast Cell–deficient KitW-sh “Sash” Mutant Mice Display Aberrant Myelopoiesis Leading to the Accumulation of Splenocytes That Act as Myeloid-Derived Suppressor Cells

Abstract

Mast cell-deficient KitW-sh “sash” mice are widely used to investigate mast cell functions. However, mutations of c-Kit also affect additional cells of hematopoietic and nonimmune origin. In this study, we demonstrate that KitW-sh causes aberrant extramedullary myelopoiesis characterized by the expansion of immature lineage-negative cells, common myeloid progenitors, and granulocyte/macrophage progenitors in the spleen. A consistent feature shared by these cell types is the reduced expression of c-Kit. Populations expressing intermediate and high levels of Ly6G, a component of the myeloid differentiation Ag Gr-1, are also highly expanded in the spleen of sash mice. These cells are able to suppress T cell responses in vitro and phenotypically and functionally resemble myeloid-derived suppressor cells (MDSC). MDSC typically accumulate in tumor-bearing hosts and are able to dampen immune responses. Consequently, transfer of MDSC from naive sash mice into line 1 alveolar cell carcinoma tumor-bearing wild-type littermates leads to enhanced tumor progression. However, although it can also be observed in sash mice, accelerated growth of transplanted line 1 alveolar cell carcinoma tumors is a mast cell–independent phenomenon. Thus, the KitW-sh mutation broadly affects key steps in myelopoiesis that may have an impact on mast cell research.

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

“…It recently has been reported that there are abnormalities in populations of myeloid-derived suppressor cells (MDSCs) in Kit W−sh/W−sh mice (Michel et al, 2013). However, it is unclear whether any problems with MDSCs contribute to disease exacerbation in Kit W−sh/W−sh mice in the EAE models tested.…”

Dissociation of immunosuppressive and nociceptive effects of fentanyl, but not morphine, after repeated administration in mice: Fentanyl-induced sensitization to LPS

“…The finding that W-sh mice produced lower, but significant amounts of TNFa after LPS suggests that other cell populations in the peritoneal cavity (such as macrophages) are responsible for this response. In this respect, the Kit W sh mutation causes myelopoiesis alterations characterized by the expansion of granulocyte/macrophage progenitors in the spleen (Michel et al, 2013).…”

Mast cells in rheumatic disease

“…In addition, KitWKitW-v mice had normal arthritis development in the collagen induced arthritis model (Pitman et al, 2011). Unlike neutropenic KitWKitW-v mice, KitWÀ sh/WÀ sh mice have a baseline pro-inflammatory phenotype, including neutrophilia (Michel et al, 2013;Nigrovic et al, 2008). Therefore, these confounding results have sometimes been attributed to the neutrophilia in KitWÀ sh/WÀ sh mice, which renders them insensitive to mast cell-mediated neutrophil recruitment, a critical event in early arthritis development (Brown and Hatfield, 2012).…”