## 9 RIPK1-Mediated Inflammatory Diseases  
Many human inflammatory and neurodegenerative diseases are associated with abnormal RIPK1 expression or activity. Reports of gene mutations or non-genetic factors that affect RIPK1 activity are accumulating, highlighting the importance of RIPK1 regulation in human diseases.  
Reduced RIPK1 expression can lead to various human diseases, largely due to the hyperactivation of RIPK3, ZBP1, and Caspase-8. As discussed previously, RIPK1 neutralizes RIPK3 and ZBP1 through RHIM domain interaction under normal conditions, and loss of RIPK1 leads to overactivation of ZBP1 and RIPK3, resulting in excessive necroptosis and systemic inflammation. In the meantime, RIPK1 inhibits FADD/Caspase-8-mediated apoptosis through death domain interaction during development, and loss of RIPK1 leads to excessive apoptosis. In humans, rare homozygous loss-of-function (LoF) mutations in RIPK1, including missense, nonsense, and frameshift mutations, cause combined immunodeficiency and inflammatory bowel disease (IBD). Many of these patients also suffer from lymphopenia, recurrent infections, and arthritis [110; 111; 112; 113].  
Conversely, elevated RIPK1 activity is also implicated in various human diseases due to heightened inflammation and cell death. For instance, rare mutations in RIPK1, such as D324N, D324H, and D324Y at the Caspase-8 recognition site LQLD, block Caspase-8-mediated cleavage of RIPK1, resulting in an autosomal-dominant autoimmunity disease, characterized by recurrent fevers and lymphadenopathy [114; 115; 116]. Patients with these variants often have increased pro-inflammatory cytokines and chemokines, such as IL-6, TNF, and CXCL/3, and their peripheral blood mononuclear cells are hypersensitive to RIPK1 activation-dependent apoptosis and necroptosis induced by TNF.  
Furthermore, mutations in other genes that result in hyperactivation of RIPK1 kinase activity also lead to human diseases. For instance, monogenic mutations in genes such as _IKBKG_ (encoding NEMO), _TNIP1_ (encoding ABIN1), _TNFAIP3_ (encoding A20), and members of the _LUBAC_ complex have been linked to auto-immune and inflammatory disorders, such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, and multiple sclerosis [117; 118; 119; 120]. Interestingly, these genes are also involved in regulating NF-kB signaling [121]. Animal model studies have demonstrated that genetic or pharmacological inhibition of RIPK1 kinase activity can alleviate pathological symptoms, indicating that the pathogenesis resulting from these mutations may be driven more by dysregulated RIPK1-dependent cell death rather than a failure to activate NF-kB [35; 60].  
Several chronic neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), are also linked to increased activation of RIPK1 [122; 123; 124]. For example, mutations in the _optimeurin_ (_OPTN_) gene have been implicated in human ALS. In mouse models, loss of _OPTN_ leads to elevated RIPK1 activity, as well as downstream RIPK3 and MLKL activation, resulting in axon degeneration, which is partially rescued by _Ripk3_ loss-of-function or treatment with a RIPK1 inhibitor necrostatin [122]. Furthermore, an aging-induced reduction in TAK1 expression combined with _TBKI_ mutations promotes the onset of neurodegenerative diseases, including ALS and frontotemporal dementia (FTD). This is mainly attributed to the hyperactivation of RIPK1, due to decreased inhibitory phosphorylation resulting from reduced activity of TAK1 and TBK1. Importantly, the ALS/FTD phenotype is partially rescued by a single allele of kinase-dead RIPK1 [32].