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The goal of our research is to investigate the role of inflammation in pathological processes and the cellular responses involved in this program. Understanding this system is critical, not only because of its importance in defense against infection and tissue damage, but also because the uncontrolled production of inflammatory mediators during sterile inflammatory pathologies is a major cause of many diseases, including rheumatoid arthritis, psoriasis, lupus, septic shock and malaria. We have shown that IL-1, IL-1, TNF, and CD40 as well as Pathogen- and Damage associated molecular patterns (PAMPs, DAMPs), that activate the different TLRs induce the phosphorylation of Erk1/2, a kinase with multiple substrates, through the intracellular signal cassette IKK-Cot/tpl2-MKK1/2. During these years our efforts have been also directed towards how this axis regulates the activation state of other intracellular pathways that eventually lead to an increase in the extracellular media of inflammatory mediators, such as cytokines and chemokines. To fully understand the inflammation process, whole animal models have to be used, therefore, we decided to generate a Cot/tpl2-/- and a Cot/tpl2 KD mouse. Thanks to these tools we have been able to show that Cot/tpl2 has a role in inflammatory nociception, Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis in mice as well in the generation of sterile inflammation generated by toxic doses of Acetaminophen (paracetamol). Our proposes in the future is to further elucidate the molecular mechanisms that modulate inflammatory processes and to translate the knowledge acquired in animals to humans.