Elucidating CD47-SHP1 biology to understand autoinflammatory disorders

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ABSTRACT Neutrophilic dermatosis is a spectrum of skin disorders that include several rare diseases such as Sweet’s syndrome, pyoderma gangrenosum and subcorneal pustular dermatosis [1]. The treatment options for these rare diseases hallmarked by skin lesions filled with neutrophils are limited to the use of strong immunosuppressive, which are non-specific and have adverse side effects. Thus, specific novel therapeutic targets are much needed to help patients suffering from these disorders. Mice carrying a single point mutation in the Ptpn6 gene that results in a Y208N substitution in the Ptpn6 encoded SHP1 protein (known as Ptpn6spin mice), develop spontaneous footpad inflammation that mimics neutrophilic dermatosis. We have extensively studied Ptpn6spin mice and identified several novel therapeutic targets including IL-1 alpha, RIPK1, SYK and TAK1, that can be potentially beneficial to neutrophilic dermatosis patients [2]. Building upon these prior discoveries, we have set our goals to elucidate the role of an integrin-associated protein, CD47, and its crosstalk with SHP1 in regulating autoinflammatory disease and health. CD47 is ubiquitously expressed in the human body and provides a “don’t eat me” signal to the phagocytic cells [3, 4]. Our preliminary data show a crucial role for CD47 in regulating disease observed in Ptpn6spin mice; however, the cellular and molecular mechanisms remain unknown. Understanding the cellular and molecular basis of these pathologies will not only enhance our general understanding of CD47 and SHP1 biology, but also aid in the development of potential novel therapies for inflammation and cancer.