An ENU Mutagenesis-Derived Mouse Model with a Dominant Jak1 Mutation Resembling Phenotypes of Systemic Autoimmune Disease

Abstract

Within the Munich, Germany, N-ethyl-N-nitrosourea mouse mutagenesis program, we isolated a dominant Jak1 mouse model resembling phenotypic characteristics related to autoimmune disease. Chromosomal sequencing revealed a new Jak1 (p.Ser645Pro) point mutation at the conserved serine of the pseudokinase domain, corresponding to a somatic human mutation (p.Ser646Phe) inducing a constitutive activation of the Janus kinase (JAK)/STAT pathway. Morphologically, all Jak1(S645P+/-) mice showed a progressive structural deterioration of ears starting at the age of 4 months, with mononuclear cell infiltration into the dermis. Female mutant mice, in particular, developed severe skin lesions in the neck from 7 months of age. The IHC analysis of these lesions showed an activation of Stat3 downstream to Jak1(S645P) and elevated tissue levels of IL-6. Histopathological analysis of liver revealed a nodular regenerative hyperplasia. In the spleen, the number of Russell bodies was doubled, correlating with significant increased levels of all immunoglobulin isotypes and anti-DNA antibodies in serum. Older mutant mice developed thrombocytopenia and altered microcytic red blood cell counts. Jak1(S645P+/-) mice showed phenotypes related to impaired bone metabolism as increased carboxy-terminal collagen cross-link-1 levels and alkaline phosphatase activities in plasma, hypophosphatemia, and strongly decreased bone morphometric values. Taken together, Jak1(S645P+/-) mice showed an increased activation of the IL-6-JAK-STAT pathway leading to a systemic lupus erythematosus-like phenotype and offering a new valuable tool to study the role of the JAK/STAT pathway in disease development.

Hyperactivation of JAK1 tyrosine kinase induces stepwise, progressive pruritic dermatitis

“…Nonetheless, WT BM cells transferred into Spade-mutant jci.org Volume 126 Number 6 June 2016 mice should be a useful model to investigate the presymptomatic pathological changes in the skin under emollient treatment, which is difficult to investigate in humans. While the present article was in preparation, Sabrauski et al reported that a missense point mutation (S645P) in the pseudokinase domain of the Jak1 gene resulted in dermatitis accompanied by STAT3 activation (41). However, there are important differences between our results and theirs with respect to disease onset and phenotype.…”

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

“…This could explain the earlier failure of the JAK3/SYK blocking agent R333 in a clinical CLE study (45). A central role for JAK1 in CLE-associated immune signaling also is supported by recent findings of mice developing CLE-like skin lesions due to JAK1-hyperactivation (46). Currently, a phase II clinical trial investigates the efficacy of orally administered JAK1 inhibitor filgotinib in female patients with active CLE (NCT03134222).…”

Interactions of the immune and sensory nervous systems in atopy

“…These targets may include TRP channels, as previous studies have demonstrated, these proteins can be phosphorylated to modulate neuronal activity . Strikingly, recent studies in both mice and humans have identified activating mutations in JAK1 that result in pruritic dermatoses . Bone marrow transplantation with wild‐type bone marrow into mutant JAK1 mice, as well as potent systemic immunosuppression in patients with activated mutant JAK1, did not resolve the aberrant inflammation and chronic itch.…”