Roles of Ubiquitin Sensor ABIN-1 In The Immune System
- Author(s): Callahan, Joseph Aaron
- Advisor(s): Ma, Averil
- et al.
Heterologous expression of ABIN-1 (A20 Binding and Inhibitor of NF-kB-1, gene name Tnip1), like A20, was suggested to restrict TNF-induced inflammation and cell death. ABIN-1's physiological function was unknown. To interrogate ABIN-1's roles in vivo, we generated ABIN-1-deficient mice. ABIN-1 was required for successful embryonic development. TNF-deficiency rescued this lethality, demonstrating that ABIN-1 restricts potentially lethal TNF-induced signals. ABIN-1-/- TNF-/- mice develop a striking immune phenotype, suggesting that ABIN-1 restricts TNF-independent signals. ABIN-1-/- TNF-/- RAG-1-/- mice have splenomegaly, which supports that ABIN-1 expression in innate cells preserves immune quiescence. ABIN-1-/- fetal liver chimera develop partially cell-intrinsic widespread immune activation, suggesting that ABIN-1-/- hematopoietic cells are sufficient for exaggerated immune activation.
Aberrant immune activation contributes to the pathogenesis of multiple autoimmune and inflammation-exacerbated diseases. The Tnip1 gene is strongly associated with susceptibility to psoriasis in humans. Psoriasis is a chronic, inflammatory skin disease caused by a combination of environmental and genetic factors. We demonstrated that mice lacking ABIN-1 specifically in dendritic cells (DCs), ABIN-1Flox CD11c-Cre mice, exhibited perturbed immune homeostasis. ABIN-1 deficient DCs displayed exaggerated NF-kB and MAP kinase signaling and produced more IL-23 than normal cells in response to TLR ligands. Challenge of ABIN-1Flox CD11c-Cre mice with topical TLR7 ligand lead to greater numbers of TH17 and gamma delta T cells and exacerbated development of psoriaform lesions. These phenotypes were reversed by DC-specific deletion of the TLR adaptor MyD88. These studies link ABIN-1 with IL-23 and IL-17, and provide cellular and molecular mechanisms by which ABIN-1 regulates susceptibility to psoriasis. They support that ubiquitin sensor ABIN-1 regulates cell survival and restricts proinflammatory signals in DC to protect against psoriasis.