Wiskott–Aldrich syndrome protein (WASP) regulates anti-inflammatory macrophages in mice and humans and is critical for maintenance of mucosal homeostasis

Patients with Wiskott-Aldrich syndrome develop recurrent infections, thrombocytopenia and eczema. Additionally, the majority of patients develop autoimmune sequalae and up to 10% of patients develop inflammatory bowel disease (IBD). WASP-deficient (Was^-/-) mice similar to human also develop spontaneous colitis. We found that WASP is critical for innate immune cell-mediated maintenance of intestinal homeostasis. Recently WASP was identified in an IBD causal sub-network and predicted to have potential role in regulating anti-inflammatory macrophage (Mφ) function (Jostins et al., Nature 2012). Therefore, we investigated the role of WASP in the generation/function of anti-inflammatory Mφ. Compared to wild-type mice, pre-colitic 5-week old Was^-/- mice had an increased percentage of pro-inflammatory Mφ (Ly6c^hiMHCII^hi) and concomitant decrease in anti-inflammatory Mφ (Ly6c^-/lowMHCII^hi) in the gut. Similarly, in mixed bone-marrow chimera experiment Was^-/- compartment had more pro-inflammatory Mφ and less anti-inflammatory Mφ in the gut compared to wild-type compartment.  In addition in vitro generation of M2 Mφ from bone marrow derived Mφ was also aberrant in Was^-/- mice. Was^-/- M2 Mφ produced more pro-inflammatory cytokines and induced higher T cell proliferation, and less Treg generation compared to WT M2 Mφ. We also observed that only WT M2 Mφ, but not Was^-/- M2 Mφ, protected against colitis mediated by CD4⁺ T cells in Was^-/-Rag2^-/- mice. Similarly, the generation of M2 Mφ was also impaired in WAS patients producing elevated pro-inflammatory cytokines and were less efficient in promoting Treg generation. These data suggest that WASP plays a critical role in generation/function of anti-inflammatory Mφ in both mice and humans.