Dendritic cells (DCs) are innate immune cells that regulate both immune homeostasis as well as antigen driven immune responses. The functions of DCs are highly regulated by signals initiated by Toll-like receptors (TLRs). Consequently, intracellular molecules that regulate TLR signaling pathways are pivotal for regulating host immune responses. We have recently found that A20 is a ubiquitin modifying enzyme that restricts toll-like receptor (TLR) induced signals. We are studying the roles of A20 expression in DCs in regulating immune homeostasis and responses. To accomplish this, we have generated two strains of gene targeted mice: one that disrupts the A20 gene in all cells and one in which a """"""""floxed"""""""" allele of A20 has been targeted to the endogenous A20 locus. We have interbred the """"""""floxed"""""""" mice with a novel strain of CD11-Cre transgenic mouse line that expresses Cre enzyme with high selectivity and specificity in DCs. These compound A20flox/flox CD11c-Cre mice will thus provide us with a very powerful and novel reagent for studying the role of A20 expression in DCs in regulating immune homeostasis and immune responses. We propose to use these A20flox/flox CD11-cre compound mice, as well as cells derived from both strains of mice, to determine how A20 expression in DCs regulates their responses to TLR ligands in vitro and in vivo.
The first aim will focus upon understanding the cell biology and biochemistry underlying A20's roles in regulating TLR signaling in DCs, and will elucidate the cell-autonomous functions of DCs that are regulated by A20.
The second aim will utilize A20flox/flox CD11c-Cre mice to determine how A20 expression in DCs regulates their homeostasis and activation in vivo.
This second aim will also interrogate how A20 expression in DCs regulates peripheral tolerance and immune responses.
This project focuses on a potent endogenous anti-inflammatory protein called A20, and how it regulates dendritic cell functions in vivo. As dendritic cells are powerful regulators of immune responses, and as A20 plays critical roles in regulating dendritic cell functions, understanding how A20 regulates dendritic cells and immune responses could significantly enhance the development of therapies for inflammatory diseases and thus have major benefits for public health.
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|Ma, Averil (2015) From trash collectors to guardians of cell signaling and immune homeostasis. Immunol Rev 266:1-5|
|Duong, Bao H; Onizawa, Michio; Oses-Prieto, Juan A et al. (2015) A20 restricts ubiquitination of pro-interleukin-1? protein complexes and suppresses NLRP3 inflammasome activity. Immunity 42:55-67|
|Onizawa, Michio; Oshima, Shigeru; Schulze-Topphoff, Ulf et al. (2015) The ubiquitin-modifying enzyme A20 restricts ubiquitination of the kinase RIPK3 and protects cells from necroptosis. Nat Immunol 16:618-27|
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|Ma, Averil; Malynn, Barbara A (2012) A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 12:774-85|
|Hammer, Gianna Elena; Turer, Emre E; Taylor, Kimberly E et al. (2011) Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nat Immunol 12:1184-93|
|Ashida, Hiroshi; Kim, Minsoo; Schmidt-Supprian, Marc et al. (2010) A bacterial E3 ubiquitin ligase IpaH9.8 targets NEMO/IKKgamma to dampen the host NF-kappaB-mediated inflammatory response. Nat Cell Biol 12:66-73; sup pp 1-9|
|Malynn, Barbara A; Ma, Averil (2010) Ubiquitin makes its mark on immune regulation. Immunity 33:843-52|
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