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SHP-1 (PTPN6) keeps the inflammation at bay: limiting IL-1α-mediated neutrophilic dermatoses by preventing Syk kinase activation

Cellular & Molecular Immunology volume 14, pages 881–883 (2017)Cite this article

Autoinflammatory syndrome (AIS) is characterized by periodic inflammation in the absence of infection, autoantibodies or self-reactive lymphocytes. Therefore, AIS has defining characteristics that differ from those of autoimmune diseases. The sterile inflammation observed in AIS is likely caused by the dysregulation of the innate immune system. However, the etiologies and physiopathologies of these autoinflammatory disorders remain ambiguous. Uncontrolled interleukin (IL)-1 biosynthesis, which is initiated by danger signals in the inflammasome or via nucleic acid-sensing pathways, has been suggested to have a critical role in AISs such as Behçet’s disease, Familial Mediterranean fever and Cryopyrin-associated periodic syndrome. In addition, other proinflammatory cytokines, including TNF-α, Type-I interferons and IL-18, have been implicated in organ-specific inflammation in AISs. In clinical studies, colchicine and anti-TNF-α mAb have been used to treat AIS patients, and IL-1 blockade therapies (treatment with IL-1R inhibitor or anti-IL-1β mAb) significantly reduced disease progression and induced sustained remission in a substantial number of patients.1 Unfortunately, some patients still have poor responses to these therapies, and their diseases progress with multi-organ inflammation. Thus, scientists continue to search for new strategies with higher efficiency for AIS patients.

Neutrophilic dermatoses, including Sweet’s syndrome, pyoderma gangrenosum and subcorneal pustular dermatosis, are a group of inherited AISs that present with excessive neutrophil infiltration in the skin lesions. In past years, the mutation of Ptpn6 gene, which encodes a phosphatase PTPN6 (protein tyrosine phosphatase nonreceptor type 6) or SHP-1 (Src homology region 2 (SH2) domain-containing protein phosphatase), has been linked to not only neutrophilic dermatoses but also autoimmune diseases and hematological malignancies in humans.2 In mice, several Ptpn6 mutants have been identified and characterized. A loss of PTPN6 in mice (motheaten, Ptpn6me/me) results in severe systemic inflammation and death by 3 to 4 weeks of age. Compared to Ptpn6me/me mice, Ptpn6me-v/me-v (motheaten-viable, a T-to-A transversion at a splice consensus site) mice also develop myeloproliferative disease but die at ~9 to 10 weeks of age. However, Ptpn6meb2/meb2 (insertion of a B2 element into exon 6) mice present with autoinflammatory diseases, but their life span could be prolonged to 6 to 8 months. Interestingly, hypomorphic Ptpn6spin (spontaneous inflammation, with a Y208N missense mutation in the carboxy terminus) mice can survive for 1 year and display symptoms that resemble those of neutrophilic dermatoses in human.3 Therefore, additional genetic and functional studies of PTPN6 have been facilitated by using these viable mice.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Biotechnology, Tzu Chi University, Hualian, Taiwan, China

    Ren-In You

  2. Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    Ching-Liang Chu

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  1. Ren-In You
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Correspondence to Ching-Liang Chu.

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You, RI., Chu, CL. SHP-1 (PTPN6) keeps the inflammation at bay: limiting IL-1α-mediated neutrophilic dermatoses by preventing Syk kinase activation. Cell Mol Immunol 14, 881–883 (2017). https://doi.org/10.1038/cmi.2017.59

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