Last year, Children's Hospital attached to Fudan University cured a special patient. He was a two-year-old Chinese boy, with periodic fever episodes occurring every eight to ten days and lasting for three to five days. Doctors suspected him of developing a hereditary disease, but they failed to pinpoint the specific reason.
With the advice of researchers, doctors adopted a novel therapeutic method, by which the boy experienced clinical improvement and the frequency of fevers declined significantly. This treatment was based on concerted efforts by the ZHOU Qing Lab from the Zhejiang University Life Sciences Institute and Children's Hospital attached to Fudan University. They detected the culprit behind this mysterious autoinflammatory disease-non-cleavable RIPK1 variants.
In their study, ZHOU Qing et al. identified a dominantly inherited autoinflammatory disease caused by impaired caspase-8 cleavage in RIPK1. This condition was differentiated from the previously reported recessively inherited RIPK1-deficient condition characterized by immune deficiency. By contrast, patients with one copy of mutated RIPK1 in the caspase-8 cleavage site presented with symptoms of immune dysfunction, including recurrent fevers and lymphadenopathy. This study was published online in the journal of Nature on December 11, 2019.
The data in this study highlighted the role of RIPK1 kinase activity in promoting apoptosis and necroptosis and catalyzing transcriptional production of pro-inflammatory cytokines, such as IL-6, which is a previously under appreciated aspect of RIPK1 biology. Research findings suggested that the periodic fevers of these patients may reflect the augmented production of cytokines such as IL-6 in response to what may be benign stimuli for normal individuals. Activated RIPK1 was shown to mediate transcription of pro-inflammatory cytokines in myeloid lineages, independent of cell death, in neurodegenerative diseases. In addition, cytokines such as TNF in turn can further promote cell death, thus setting in motion a vicious circle of inflammation that culminates in the development of an autoinflammatory disease.
Researchers showed that patient fibroblasts may have developed several compensatory mechanisms to fend off deleterious effects of activated RIPK1, including downregulating the expression of RIPK1 and TNFR1, as well as promoting anti-ROS mechanisms.
This research provided insights into the complex disease mechanisms behind noncleavable RIPK1 variants in humans compared to that of the mouse models. It also linked an activating RIPK1 variant to ferroptosis, which sheds light on the diverse roles of RIPK1 in regulating several cell death pathways.
