Null Function of Npr1 Disturbs Immune Response in Colonic Inflammation During Early Postnatal Stage

Inflammation. 2022 Dec;45(6):2419-2432. doi: 10.1007/s10753-022-01702-4. Epub 2022 Jul 7.

Abstract

Natriuretic peptide receptor 1 (NPR1) is conventionally known as a regulator of vascular homeostasis. Here, we generated an Npr1 knockout mouse model with CRISPR/Cas9 technology and found that homozygous mice (Npr1-/-) exhibited weight loss and poor survival rate during early postnatal stage. Careful examination revealed unexpectedly that Npr1-/- mice developed colitis characterized by shortened colon, evident colonic mucosal damage, increased histopathological score, and higher colonic expression of proinflammatory cytokines interleukin-1B (IL1B) and -6 (IL6). RNA-sequencing analysis revealed that differentially expressed genes were prominently enriched in the biological pathways related to immune response in both spleen and colon of Npr1-/- mice. Cytofluorimetric analysis demonstrated that leukocytes in the spleen were significantly increased, particularly, the populations of neutrophil and CD3+ T cell were elevated but CD4+ T cells were decreased in Npr1-/- mice. Administration of 8-Br-cGMP, a downstream activator of NPR1, restored these immune-cell populations disturbed in Npr1-/- mice and lessened the colitis-related phenotypes. To validate the involvement of Npr1 in colitis, we examined another mouse model induced by dextran sodium sulfate (DSS) and found a decreased Npr1 expression and shifted immune-cell populations as well. Importantly, 8-Br-cGMP treatment exhibited a similar effect in the restoration of immune-cell populations and attenuation of colonic inflammation in DSS mice. Our data indicate that loss of Npr1 possibly interrupts immune response, which is critical to the pathogenesis of colitis in the early life.

Keywords: CD4+ T cells; Npr1; colitis; colonic inflammation; immune response.

MeSH terms

  • Animals
  • Colitis* / pathology
  • Dextran Sulfate / toxicity
  • Disease Models, Animal
  • Immunity
  • Inflammation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout

Substances

  • Dextran Sulfate
  • 8-bromoguanosino-3',5'-cyclic monophosphorothioate