New roles of the Lyn tyrosine kinase in psoriasis development and cell death

Abstract : The Src family kinase, of which Lyn is one member, plays a key role in controlling many biological processes. Lyn has a well-established function in hematopoietic cells, presenting an important role in the regulation of hematopoietic abnormalities. In fact, Lyn plays a key role in maintaining several kind of leukemia, and furthermore it expression is altered in solid tumors. Different studies have shown that Lyn has an anti-apoptotic role. Lyn can be cleaved by caspases, cysteine proteases involved in apoptosis and inflammation, giving a new protein with a cytosolic location, different from the WT and membrane-anchored form. We have shown that the cytosolic form of Lyn (cLyn) regulated Bim, a pro-apoptotic member of the Bcl-2 family, involved in the control of mitochondrial apoptosis. We have identified that Bim is phosphorylated on tyrosine 92 and 161 by Lyn, resulting in an inhibition of its pro-apoptotic function, increasing its interaction with anti-apoptotic members such as Bcl-XL, thus limiting the permeabilization of mitochondrial outer membrane and impairing cell apoptosis. Lyn also has a pro-inflammatory role. We have previously shown that overexpression of the caspase-cleaved form of Lyn, in mice, leads to an inflammatory skin syndrome, resembling human psoriasis. Based on this result, we wanted to know if Lyn played a role in this chronic skin disease. Analysis of Lyn's expression in psoriasis patients showed that Lyn was overexpressed in lesional skin compared to non-lesional or healthy skin, which was subsequently confirmed in two mouse models of psoriasis disease. Interestingly, we have shown that the increase in Lyn expression is in both the dermis and the epidermis in humans and in mice, indicating that recruitment of immune cells into lesional skin but also the modulation of Lyn in keratinocytes are involved. To determine the role of Lyn in this skin disease we induced a psoriasis-like phenotype in Lyn deficient mice. A significant reduction in cutaneous phenotype was observed in LynKO mice compared to WT mice, identifying Lyn as a new player in the pathogenesis of psoriasis. In addition, our results established that Lyn expression in keratinocytes seemed crucial and sufficient for the maintenance of the psoriasis phenotype, indicating a new role of Lyn in the regulation of keratinocytes. During this work, we observed that inflammatory caspases were activated in lesional skin from psoriasis patients. Inflammatory caspases, following their activation within the inflammasome, will cleave IL-1β and IL-18, leading to their maturation. We then wanted to know if inflammatory caspases participated in the development of psoriasis. We were able to show that when we induced a psoriasis-like disease in mice, the invalidation of inflammatory caspases or its pharmacological inhibition significantly reduced the development of the disease compared to WT mice. Although immune cells and keratinocytes were able to secrete IL-1β via activation of the inflammasome, our data established that only activation of inflammatory caspases in the immune system seemed necessary for a complete inflammatory response. In summary, my thesis shows a molecular mechanism by which Lyn tyrosine kinase negatively regulates the mitochondrial apoptotic pathway, which may contribute to the transformation and/or chemotherapeutic resistance of cancer cells. On the other hand, our results show that Lyn could be an important regulator of psoriasis and our study indicates that inflammatory caspases activated in immune cells are involved in the pathogenesis of psoriasis. To date, although several treatments have been developed for psoriasis, the disease remains unresolved, so the development of therapeutic targets against Lyn and inflammatory caspases could be of interest for the treatment of the disease.
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Lazaro Emilio Aira Diaz. New roles of the Lyn tyrosine kinase in psoriasis development and cell death. Cellular Biology. Université Côte d'Azur, 2018. English. ⟨NNT : 2018AZUR4027⟩. ⟨tel-02275787⟩

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