The molecular role of CARMA2 in psoriasis

• Applicant: Professor Dr. Stephan Hailfinger
• Subject Area: Dermatology
• Term: from 2014 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255227348

Patients suffering from psoriasis have multiple symptoms like skin lesions and psoriatic arthritis that can lead to lifelong suffering. The exact cause of psoriasis is unknown, but a complex positive feedback loop between keratinocytes and immune cells sustains the disease. Gene variations associated with psoriasis can be grouped into two classes, namely genes involved in the immune response (like HLA-Cw0602* or IL-23R) and genes that influence the state of keratinocytes (like CARMA2).CARMA2 is a signaling protein that potently activates NF-kB, a transcription factor with pro-inflammatory and proliferation-promoting functions. A close homologue of CARMA2, CARMA1, plays an essential role in the activation of lymphocytes. Oncogenic CARMA1 mutations have been identified in an aggressive subtype of diffuse large B cell lymphomas that are characterized by constitutive NF-kB activation. Similar mutations in CARMA2 were recently found in psoriasis patients, suggesting that hyperactive CARMA2 mutations are promoting the keratinocyte-dependent inflammatory aspect of psoriasis. In the proposed project, we would like to assess whether CARMA2 mutants found in psoriasis patients have the capacity to activate the protease MALT1, a key signal transducer acting downstream of CARMA1 in the immune response. We hypothesize that inhibition of MALT1 will suppress the CARMA2-dependent activation of keratinocytes and at the same time dampen the local immune response, which should efficiently break the perpetual cycle of cellular activation in the inflamed psoriatic skin. To explore these possibilities, we will investigate signaling pathways and gene expression profiles induced by CARMA2 mutations in keratinocytes, and determine how these events contribute to the development of psoriasis. To explore the therapeutic potential of MALT1 inhibitors as a treatment option for psoriasis, we will provoke psoriasis in wild-type, MALT1-deficient and MALT1 protease-inactive mice and monitor the onset, kinetics and development of the disease. Moreover, we will assess the effect of topical application of two previously described MALT1 inhibitors. Collectively, these approaches will improve our understanding of the molecular and biological functions of CARMA2 and MALT1. Moreover, our findings may identify novel therapeutic strategies for the treatment of psoriasis.

• DFG Programme: Independent Junior Research Groups