RIPK3-dependent necroptosis is the primary cause of RIPK1-deficient-induced immunodeficiency.

Abstract

RIPK1 (receptor-interacting serine/threonine kinase 1) plays a pivotal role in developing the immune system--patients with homozygous loss-of-function mutations of RIPK1 present with immunodeficiency and intestinal inflammation. Here, we reported that RIPK1-deficient rats represented defects of human patients and were certified as a suitable disease model. Knocking out Ripk3 rather than Caspase-8 nearly completely corrected immunodeficiency disorders, developmental defects, and necroptosis in the thymus of RIPK1-deficient rats. However, inflammatory enteritis was still detected in either Ripk1/Ripk3-or Ripk1/Casp-8-double deficient rats and only rescued in Ripk1/Ripk3/Caspase-8-triple deficient rats, suggesting RIPK3 mediated necroptosis and Caspase-8 dependent apoptosis contribute in different part in RIPK1-deficient caused the syndrome. Moreover, RIPK1-deficient rat dermal fibroblasts (RDFs) showed sensitive necroptosis and impaired NF-{kappa}B activation, also reported in RIPK1-deficient human patients. And pharmacological inhibition of NF-{kappa}B activation could sensitize necroptosis of rat cells. Since mutations that damage NF-{kappa}B activation could cause immunodeficiency in human patients, it suggested that aberrantly activated necroptosis play a vital role in certain kinds of primary immunodeficiency syndromes and pharmacological inhibition of necroptosis could be a novel therapeutic strategy for those diseases.