IL-1 plays a significant role in inflammation in a variety of forms of inflammatory arthritis, including gouty arthritis, Systemic-onset Juvenile idiopathic arthritis and adult-onset Still's disease and mediates synovial inflammation, cartilage destruction, and premature mortality. The central role that IL-1 plays in these diseases is strongly emphasized by studies in IL-1 signaling deficient mice and in patients administered anti-IL-1 biologicals. IL-1 is primarily produced by inflammasomes in macrophages (M?) and in arthritis also by serine proteases in neutrophils and mast cells. ASC is the essential inflammasome adaptor composed of PYRIN (PYD) and Caspase recruitment domains (CARD), which are essential for its function as inflammasome adaptor. However, the mechanism regulating the excessive release of IL-1 in inflammatory arthritis is poorly understood, but has tremendous potential for developing future therapies. We discovered a family of small endogenous inflammasome inhibitors composed of only a PYD, which we refer to as PYD-only proteins (POPs). In vitro studies show that POP1 interacts with the PYD of ASC and thereby disrupts the essential PYD-PYD interaction necessary for inflammasome formation and release of IL-1. Our preliminary in vivo studies further support a central role of POP1 in maintaining a balanced inflammasome response necessary for homeostasis and preventing chronic inflammation, such as in inflammatory arthritis. However, POPs have not been studied in vivo, because POPs are lacking from mice and evolved in humans as central immune regulatory proteins. We generated unique transgenic (TG) mice expressing POP1 specifically in M? and dendritic cells (DC) and therefore now in the position to undertake these lacking in vivo studies and we further provide now the urgently needed first conditional inflammasome mouse model to study inflammatory and auto-immune disease contribution of M?and DC. The objective of this application is to investigate the mechanism by which POP1 blocks inflammatory arthritis as part of a negative feedback mechanism, using experimental IL-1 -dependent inflammatory arthritis mouse models and M? from human arthritis patients. Our rationale for this research is that understanding the POP1-mediated regulation of inflammatory arthritis, might allow the development of novel therapeutic approaches to ameliorate inflammatory arthritis. In addition, our study will provide novel insights into the regulation of arthritis and other inflammatory diseases by provide the first in vivo data for a POP family member and a first conditional inflammasome analysis.
IL-1 plays an important role in a variety of forms of inflammatory arthritis, including gouty arthritis and adult-onset Still's disease and mediates synovial inflammation, cartilage destruction, and premature mortality and is a huge burden for our health care system. IL-1 is primarily produced by inflammasomes in macrophages and we discovered a novel inflammasome inhibitor, which protects from systemic inflammatory disease. By studying the molecular mechanism by which this inhibitor ameliorates inflammatory arthritis in experimental mouse models, patient samples and through evaluating a novel treatment strategy based on it, we expect to positively affect human health and to significantly advance our understanding of the pathology of inflammatory arthritis and the underlying derailed innate immune mechanisms.
| Indramohan, Mohanalaxmi; Stehlik, Christian; Dorfleutner, Andrea (2018) COPs and POPs Patrol Inflammasome Activation. J Mol Biol 430:153-173 |
| Chu, Lan H; Indramohan, Mohanalaxmi; Ratsimandresy, Rojo A et al. (2018) The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat Commun 9:996 |
| Ratsimandresy, Rojo A; Chu, Lan H; Khare, Sonal et al. (2017) The PYRIN domain-only protein POP2 inhibits inflammasome priming and activation. Nat Commun 8:15556 |
| Khare, Sonal; Radian, Alexander D; Dorfleutner, Andrea et al. (2016) Measuring NLR Oligomerization I: Size Exclusion Chromatography, Co-immunoprecipitation, and Cross-Linking. Methods Mol Biol 1417:131-43 |
| de Almeida, Lucia; Dorfleutner, Andrea; Stehlik, Christian (2016) In vivo Analysis of Neutrophil Infiltration during LPS-induced Peritonitis. Bio Protoc 6: |
| de Almeida, Lucia; Dorfleutner, Andrea; Stehlik, Christian (2016) ASC-particle-induced Peritonitis. Bio Protoc 6: |
| Dorfleutner, Andrea; Stehlik, Christian (2016) A dRAStic RHOAdblock of Pyrin inflammasome activation. Nat Immunol 17:900-2 |
| Cuda, Carla M; Misharin, Alexander V; Khare, Sonal et al. (2015) Conditional deletion of caspase-8 in macrophages alters macrophage activation in a RIPK-dependent manner. Arthritis Res Ther 17:291 |
| de Almeida, Lucia; Khare, Sonal; Misharin, Alexander V et al. (2015) The PYRIN Domain-only Protein POP1 Inhibits Inflammasome Assembly and Ameliorates Inflammatory Disease. Immunity 43:264-76 |
| Radian, Alexander D; Khare, Sonal; Chu, Lan H et al. (2015) ATP binding by NLRP7 is required for inflammasome activation in response to bacterial lipopeptides. Mol Immunol 67:294-302 |
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