Spontaneous Insertion of a B2 Element in the Ptpn6 Gene Drives a Systemic Autoinflammatory Disease in Mice Resembling Neutrophilic Dermatosis in Humans

Abstract

We found a spontaneous autosomal mutation in a mouse leading to neutrophil infiltration with ulceration in the upper dermis of homozygous offspring. These animals had increased neutrophil numbers, associated with normal lymphocyte count, in peripheral blood and bone marrow, suggesting a myeloproliferative disorder; however, granulocyte precursor proliferation in bone marrow was actually reduced (because circulating neutrophils were less susceptible to apoptosis). Neutrophil infiltration of the skin and other organs and high serum levels of immunoglobulins and autoantibodies, cytokines, and acute-phase proteins were additional abnormalities, all of which could be reduced by high-dose corticosteroid treatment or neutrophil depletion by antibodies. Use of genome-wide screening localized the mutation within an 0.4-Mbp region on mouse chromosome 6. We identified insertion of a B2 element in exon 6 of the Ptpn6 gene (protein tyrosine phosphatase, non-receptor type 6; also known as Shp-1). This insertion involves amino acid substitutions that significantly reduced the enzyme activity in mice homozygous for the mutation. Disease onset was delayed, and the clinical phenotype was milder than the phenotypes of other Ptpn6-mutants described in motheaten (me, mev) mice; we designated this new genotype as Ptpn6(meB2/meB2) and the phenotype as meB2. This new phenotype encompasses an autoinflammatory disease showing similarities to many aspects of the so-called neutrophilic dermatoses, a heterogeneous group of skin diseases with unknown etiology in humans.

Beyond canonical inflammasomes: emerging pathways in IL-1-mediated autoinflammatory disease

“…Mutation in the phosphatase, SHP-1, causes a severe autoinflammatory syndrome that resembles neutrophilic dermatosis in humans and is characterized by persistent footpad swelling and suppurative inflammation [52–55]. Excessive production of inflammatory cytokines, neutrophilia and hyperactive T cell responses are associated with this SHP-1-mediated disease pathology [56, 57]. Genetic abrogation of IL-1R was found to protect SHP-1 mutant mice from cutaneous inflammation [58], suggesting that IL-1-mediated events potentiate disease.…”

Tyrosine Kinase SYK Licenses MyD88 Adaptor Protein to Instigate IL-1α-Mediated Inflammatory Disease

“…Ptpn6 spin mice display a similar myeloproliferative disorder and footpad inflammation as the motheaten mice; however, unlike the motheaten mice, Ptpn6 spin mice survive into adulthood (Croker et al, 2008). Moreover Ptpn6 spin mice develop persistent footpad swelling and suppurative inflammation that is very similar to neutrophilic dermatosis in humans (Croker et al, 2008; Nesterovitch et al, 2011). While the essential roles of interleukin (IL)-1 in promoting these autoinflammatory diseases are well established, it is only recently that the specific roles for IL-1α and IL-1β have been recognized (Lukens et al, 2014; Lukens et al, 2013).…”

SHP-1 and IL-1α conspire to provoke neutrophilic dermatoses

“…This association between mutations in Ptpn6 and clinic cases of neutrophilic dermatoses highlights the value of Ptpn6 mutant mice in the study of physiological autoinflammatory skin disorders. Indeed, utilization of SHP-1 deficient mice has significantly aided in the elucidation of the cellular and molecular players that contribute to tissue damage and inflammation in neutrophilic dermatosis and other autoinflammatory skin disorders 5 , 22 …”