Proinflammatory Pathways Are Activated in the Human Q344X Rhodopsin Knock-In Mouse Model of Retinitis Pigmentosa

Biomolecules. 2021 Aug 6;11(8):1163. doi: 10.3390/biom11081163.


Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.

Keywords: JAK/STAT; NLRP3; TNFα, NF-κB; inflammation; microglia; retinal degeneration; retinitis pigmentosa; rhodopsin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Antirheumatic Agents / pharmacology*
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / immunology
  • Endothelium, Vascular / pathology
  • Gene Expression
  • Gene Knock-In Techniques
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / genetics
  • Janus Kinases / immunology
  • Leukemia Inhibitory Factor / pharmacology*
  • Mice
  • Mice, Transgenic
  • Microglia / drug effects
  • Microglia / immunology
  • Microglia / pathology
  • Mutation*
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Retina / drug effects*
  • Retina / immunology
  • Retina / pathology
  • Retinitis Pigmentosa / drug therapy*
  • Retinitis Pigmentosa / genetics
  • Retinitis Pigmentosa / immunology
  • Retinitis Pigmentosa / pathology
  • Rhodopsin / deficiency
  • Rhodopsin / genetics*
  • STAT Transcription Factors / antagonists & inhibitors
  • STAT Transcription Factors / genetics
  • STAT Transcription Factors / immunology
  • Signal Transduction
  • Transgenes
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • Antirheumatic Agents
  • Heterocyclic Compounds, 3-Ring
  • Leukemia Inhibitory Factor
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • STAT Transcription Factors
  • Tumor Necrosis Factor-alpha
  • upadacitinib
  • Rhodopsin
  • Janus Kinases