Teresa Fernandes-Alnemri, PhD
Philadelphia, PA 19107
(215) 923-1098 fax
Research and Clinical Interests
The research in my lab focuses on the signaling pathways involved in caspase-1 activation and pro-inflammatory cytokine production by members of the NLR family including NLRP1, NLRP3, NLRC4, NOD1 & NOD2, and the interferon-induced protein AIM2 (absent in melanoma 2).
We are interested in how NLR proteins and other cytosolic danger sensors such as AIM2 can recognize microbial pathogen- and tissue damage-derived molecular danger signals, and assemble inflammasome complexes. These complexes serve as molecular platforms to recruit and activate procaspase-1 to produce the active caspase-1, which processes pro-IL-1² and pro-IL-18 into their corresponding mature pro-inflammatory cytokines, IL-1² and IL-18.
Although pro-inflammatory cytokine production is an innate immune response important for protection against infections with different pathogens, abnormal or chronic activation of the pro-inflammatory innate immune system could lead to a wide variety of digestive diseases such as Crohns disease and autoimmune disorders afflicting the kidney, like systemic lupus erythematosus. Chronic inflammatory responses have also been implicated in anemia of inflammation and chronic disease (AI/ACD). Some of the diseases that could lead to AI/ACD include rheumatoid arthritis, lupus, diabetes, heart failure, degenerative joint disease, kidney diseases, cancer and inflammatory bowel disease (IBD) including Crohn's disease.
We also recently demonstrated that the interferon-inducible AIM2 protein functions in cytosolic surveillance of cytoplasmic dsDNA, which is produced as a consequence of infection with viral and bacterial pathogens. Activation of the AIM2 inflammasome by binding to cytosolic dsDNA results in proinflammatory cytokine production. We have generated AIM2 knock out mice, and successfully used our model system to demonstrate that AIM2 is the innate sensor of pathological DNA complexes formed when cells are infected with dangerous pathogens like the 'rabbit fever' bacteria Francisella, and viruses such as the poxvirus Vaccinia.
Because activation of AIM2 by DNA triggers a strong inflammatory response, we are actively investigating whether the antibody-DNA complexes found in systemic lupus erythematosus (SLE) are in fact recognized by AIM2. Lupus nephritis, is an inflammatory renal disease that often results in kidney failure in SLE patients. Understanding the molecular pathways that modulate these inflammatory responses in lupus patients would be paramount to designing effective therapeutics.
Most Recent Peer-Reviewed Publications
- Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death
- Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3
- Non-transcriptional regulation of NLRP3 inflammasome signaling by IL-4
- Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function
- Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome
- The mitochondrial antiviral protein MAVS associates with NLRP3 and regulates its inflammasome activity
- Restoration of ASC expression sensitizes colorectal cancer cells to genotoxic stress-induced caspase-independent cell death
- Ribotoxic stress through p38 mitogen-activated protein kinase activates in Vitro the human pyrin inflammasome
- Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging
- A novel role for the mitochondrial HTRA2/OMI protease in aging
- Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation
- Critical roles of ASC inflammasomes in caspase-1 activation and host innate resistance to Streptococcus pneumoniae infection
- Involvement of the AIM2, NLRC4, and NLRP3 inflammasomes in caspase-1 activation by Listeria monocytogenes
- Cutting edge: Mutation of Francisella tularensis mviN leads to increased macrophage absent in melanoma 2 inflammasome activation and a loss of virulence
- The AIM2 inflammasome is critical for innate immunity to Francisella tularensis
- Functional consequences of a germline mutation in the leucine-rich repeat domain of NLRP3 Identified in an atypical autoinflammatory disorder
- Anti-inflammatory compounds parthenolide and bay 11-7082 are direct inhibitors of the inflammasome
- Cutting edge: NF-κB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression
- AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA
- Chapter Thirteen Assembly, Purification, and Assay of the Activity of the ASC Pyroptosome