Autoimmune diseases affect roughly five percent of the population. Inhibitors of the pro-inflammatory cytokine TNF have revolutionised treatment of autoimmune diseases including rheumatoid arthritis and the skin disease psoriasis, and are currently the highest grossing drugs on the market.
The default action of TNF is to directly up-regulate inflammatory genes at the transcriptional level, and this is thought to drive disease. Less commonly when TNF mediated gene induction is defective, TNF can kill cells. Using a psoriasis model we investigated whether TNF mediated cell death can also cause disease.
The inactivating chronic proliferative dermatitis mutation (cpdm) in the Sharpin gene causes dermatitis in mice that resembles human psoriasis. Our group and collaborators1 have shown that sharpin regulates linear ubiquitination and this function is essential for normal gene induction by TNF and prevention of TNF induced cell death in-vitro.
Here we show that TNF deficiency completely rescues Sharpincpdm/cpdm dermatitis. In-vivo clodrosome depletion of macrophages, potent sources of TNF, was also highly protective. In epidermal keratinocytes, TNF induced both caspase-8 dependent apoptosis and RIP3 and MLKL dependent programmed necrosis (necroptosis) in-vitro. Because necroptosis is more inflammatory than apoptosis, we hypothesised that Sharpincpdm/cpdm dermatitis is caused by necroptotic cells leaking cellular contents that are phagocytosed by macrophages, triggering inflammation. However, whilst RIP3 or MLKL deficiency only partly rescued the disease, RIP3 and caspase-8 double deficiency completely rescued the disease, indicating both necroptotic and apoptotic TNF death pathways must be crippled to prevent inflammation.
Although dogma is that apoptosis is generally immunologically silent, these data suggest that excessive apoptosis can be pathogenic, and that deregulated cell death can drive disease. This also raises the possibility that in some human diseases TNF may cause inflammation by causing cell death, and not by directly inducing pro-inflammatory gene expression.