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The main focus of the Arditi Laboratory is the study of innate immunity and how it relates to inflammatory diseases and host-pathogen interactions. All of the research projects in the lab revolve around various aspects of these areas.
NLRP3 Inflammasome Activation
The NLRP3 inflammasome, a multi-component complex that facilitates maturation of IL-1β (a critical proinflammatory cytokine involved in both acute and chronic inflammatory diseases), is activated by many diverse danger signals. We have found that the mitochondria are a central hub for the various NLRP3 activation signals. NLRP3 activators lead to mitochondrial dysfunction and apoptosis. During this process, mtROS is generated, which results in damaged (oxidized) mtDNA. The oxidized mtDNA is released into the cytosol where it binds to NLRP3 and activates the NLRP3 inflammasome.
The respiratory pathogen Chlamydia pneumoniae is an obligate intracellular bacteria that causes atypical pneumonia (right). Our lab is interested in determining the innate immune mechanisms by which C. pneumoniae is detected during lung infection and what role each pathway plays in the host response to the infection. To this end we use various knockout mice in order to dissect out the contributions of Toll-like receptors, MYD88, the Nod/Rip2 signaling pathway, and the NLRP3 inflammasome /IL-1β signaling pathway.
Additionally, we are also interested in other infectious organisms such as Staphylococcus aureus, Klebsiella pneumoniae, and influenza viral infection.
Chlamydia pneumoniae has also been associated with the development and exacerbation of asthma. We have developed a mouse model whereby C. pneumoniae infection can induce antigen sensitization and subsequently lead to asthma after challenge with the same antigen. This sensitization is dependent on the severity of infection and the timing of the sensitization relative to the initial infection and to Treg numbers.
To the right is an image of goblet cell hyperplasia and airway mucus production in response to antigen challenge in the lungs. We also study various immune aspects of house dust mite-induced asthma in mouse models.
Another inflammatory disease that C. pneumoniae has been associated with is atherosclerosis.
We have shown that TLR and MYD88 signaling is involved in the development of atherosclerosis and that C. pneumoniae infection accelerates this process. We also have evidence that C. pneumoniae can signal through the TLR/MYD88 pathway and that this pathway is also important for plaque (right) development.
More recently, we have found that IL-17α plays an important proinflammatory role in atherosclerotic plaque development.
Kawasaki disease is the leading cause of acquired heart disease among children in the US and developed countries. If untreated, 25% of these children develop coronary arteritis and aneurysms. We are investigating a mouse model of Kawasaki disease (coronary arteritis) using Lactobacillus casei cell wall extract (LCCWE) injection to induce coronary arteritis, aortitis and myocarditis, and we investigate the immune mechanisms involved in the pathogenesis of this vasculitis. To the right, you can see profound inflammation and cellular proliferation at the aortic sinus of a mouse one week after given LCCWE. We have shown that lesion development is driven by mDC-T -cell interactions. The critical involvement of T -cells in this process was revealed when Rag1-/- mice failed to develop arteritis while B -cell-deficient mice did. Thus LCCWE-induced arteritis appears to involve both innate and adaptive immune processes. More recently we found an absolute requirement for the NLRP3 inflammasome and IL-1β signaling in this model of KD and published that anti-IL-1beta treatment is more efficient that the currently used IVIG in preventing coronary lesion formation in KD mouse models. Most recently we have also published that vascular injury during Kawasaki disease in mouse models (coronary arteritis) is a major risk factor for subsequent dramatic acceleration of atherosclerosis in combination with a high fat diet.
Acute Lung Injury
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) continue to be serious health risks for both healthy individuals and mechanically ventilated patients. Our lab is interested in investigating the innate immune signaling pathways involved in LPS-induced acute lung injury as well as ventilation-induced lung injury, especially investigating the role of the NLRP3 inflammasome and IL-1 signaling leading to lung injury. To the right, you can see that endothelial cell MYD88 plays a specific role in vasculature leakage into the lungs of mice as measured by Evans Blue extravasation.