1. PKN1 kinase-negative knock-in mice develop splenomegaly and leukopenia at advanced age without obvious autoimmune-like phenotypes
- Author
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Koji Kubouchi, Salman Mahmud Siddique, Shunsuke Okamura, Shingo Kamoshida, Shinobu Tamura, Tomoo Itoh, Yuka Shinmichi, Hiroyuki Ohsaki, Reiko Sugiura, Yusuke Yamashita, Takashi Sonoki, Yasushi Itoh, Hideyuki Mukai, Nana Sawada, Shunsuke Uehara, Hiroshi Matsuoka, and Kanae Nishimura
- Subjects
medicine.medical_specialty ,CD3 ,lcsh:Medicine ,Kinases ,Autoimmunity ,Spleen ,Biology ,Article ,Mice ,Internal medicine ,medicine ,Animals ,Gene Knock-In Techniques ,Phosphorylation ,Kinase activity ,lcsh:Science ,education ,Protein Kinase C ,Mice, Knockout ,education.field_of_study ,Multidisciplinary ,Leukopenia ,lcsh:R ,Age Factors ,Germinal center ,Glomerulonephritis ,Germinal Center ,medicine.disease ,Extramedullary hematopoiesis ,Protein kinase N1 ,medicine.anatomical_structure ,Endocrinology ,Splenomegaly ,biology.protein ,lcsh:Q ,medicine.symptom ,Signal Transduction - Abstract
Protein kinase N1 (PKN1) knockout (KO) mice spontaneously form germinal centers (GCs) and develop an autoimmune-like disease with age. Here, we investigated the function of PKN1 kinase activity in vivo using aged mice deficient in kinase activity resulting from the introduction of a point mutation (T778A) in the activation loop of the enzyme. PKN1[T778A] mice reached adulthood without external abnormalities; however, the average spleen size and weight of aged PKN1[T778A] mice increased significantly compared to aged wild type (WT) mice. Histologic examination and Southern blot analyses of spleens showed extramedullary hematopoiesis and/or lymphomagenesis in some cases, although without significantly different incidences between PKN1[T778A] and WT mice. Additionally, flow cytometry revealed increased numbers in B220+, CD3+, Gr1+ and CD193+ leukocytes in the spleen of aged PKN1[T778A] mice, whereas the number of lymphocytes, neutrophils, eosinophils, and monocytes was reduced in the peripheral blood, suggesting an advanced impairment of leukocyte trafficking with age. Moreover, aged PKN1[T778A] mice showed no obvious GC formation nor autoimmune-like phenotypes, such as glomerulonephritis or increased anti-dsDNA antibody titer, in peripheral blood. Our results showing phenotypic differences between aged Pkn1-KO and PKN1[T778A] mice may provide insight into the importance of PKN1-specific kinase-independent functions in vivo.
- Published
- 2019