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Programmed necrosis is a form of caspase-independent cell death whose molecular regulation is poorly understood. The kinase RIP1 is crucial for programmed necrosis, but also mediates activation of the prosurvival transcription factor NF-B. We postulated that additional molecules are required to specifically activate programmed necrosis. Using a RNA interference screen, we identified the kinase RIP3 as a crucial activator for programmed necrosis induced by TNF and during virus infection. RIP3 regulates necrosis-specific RIP1 phosphorylation. The phosphorylation of RIP1 and RIP3 stabilizes their association within the pronecrotic complex, activates the pronecrotic kinase activity, and triggers downstream reactive oxygen species production. The pronecrotic RIP1-RIP3 complex is induced during vaccinia virus infection. Consequently, RIP3/ mice exhibited severely impaired virus-induced tissue necrosis, inflammation, and control of viral replication. Our findings suggest that RIP3 controls programmed necrosis by initiating the pronecrotic kinase cascade, and that this is necessary for the inflammatory response against virus infections.

Infections are typically accompanied by inflammation and the presence of leucocytes at the infected site. Especially in pyogenic (pus generating) infections, neutrophils are the main leukocytes that arrive and that combat the infection. When the bacteria have been killed, the inflammation also has to be resolved, and this resolution involves the death of the neutrophils through the process of apoptosis. Although we know that neutrophils eventually die through apoptosis, the connection between neutrophil apoptosis and inflammation in bacterial infections has not been clear. In meningitis, bacteria gain access to the space surrounding the brain, multiply and cause inflammation. Despite antibiotic therapy, human pneumococcal meningitis often causes brain damage and death of the patient. We show here that the experimental inhibition of neutrophil apoptosis leads to much more severe clinical disease in a mouse model of bacterial (pneumococcal) meningitis. This was due to a prolonged inflammatory activity of the neutrophils. Experimental induction of neutrophil apoptosis in mice that had been infected and treated with antibiotics (mimicking human meningitis) improved the clinical condition and accelerated recovery. Experimental manipulation of neutrophil apoptosis can therefore be beneficial in acute inflammation.