Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis
Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis
Hammer GE et al., Nat. Immunol. 12:1184-1193, 2011
Speaker: Yung-Tsai Liou (劉勇材) Time: 14:00-15:00, Feb. 29, 2012
Commentator: Dr. Chrong-Reen Wang (王崇任 老師) Place: Room 601
Abstract
A20 (also named TNFAIP3) is an E3-ligase involved in negative feedback regulation of NF-kB signaling response1. Previous study revealed that 3- to 6-week-old A20-/- mice suffer from severe inflammation and tissue damages in multiple organs and succumb to death2. Dendritic cells (DCs) are crucial for the initiation of inflammation and acquired immune responses. In this paper, the authors determined high expression levels of activated DC markers, such as CD80, CD86 and CD40, in DC-specific A20 gene knockout mice (A20fl/flCD11c-Cre mice). A20 deficiency in DCs induced expansion of myeloid and lymphoid cell populations and splenomegaly in A20fl/flCD11c-Cre mice. MyD88 is an adaptor protein involved in Toll-like receptor (TLR)-mediated NF-kB signaling pathway. Interestingly, highly activated DCs and aberrant T cell activation were found inA20fl/flMyd88fl/flCD11c-Cre mice, suggesting that A20 restricts MyD88-independent signaling that upregulates the expression of costimulatory molecules on DCs and stimulates T cell activation. The authors found that, total cell number in the lymph nodes from A20fl/flMyd88fl/flCD11c-Cre mice was lower than that of A20fl/flMyd88+/+CD11c-Cre mice. LPS-stimulated A20-/-Myd88-/- DCs secreted lower levels of inflammatory cytokines, such as TNF-a and IL-6, than A20-/-Myd88+/+ DCs, indicating that A20 restricts MyD88-mediated signaling for the regulation of cytokine production in DCs. Moreover, A20fl/flCD11c-Cre mice spontaneously developed colitis and inflammatory bowel disease-associated spondyloarthritis, Together, A20 restricts both MyD88-dependent and -independent signaling in DCs to regulate DC and T cell activation and cytokine production. Thus, the expression of A20 in DCs is crucial for the regulation of immune homeostasis.
References
1. Heyninck K and Beyaert R, A20 inhibits NF-kappaB activation by dual ubiquitin-editing functions. Trends. Biochem. Sci. 30:1-4, 2005
2. Lee EG, et al., Failure to regulate TNF-induced NF-kB and cell death responses in A20-defcient mice. Science 289:2350-2354, 2000