Mechanisms of caspase-8 suppression of the RIPK1-TBK1 axis in homeostatic type I interferon production and regulation

ABSTRACT: Type-I interferons (IFNs) are an essential component of the innate immune response that are upregulated in response to infection. However, a low level of basal, or tonic, IFN expression is also critical to maintain tissue homeostasis. While the regulation of type-I IFN production during infection is well studied, the mechanisms controlling this basal expression and its impacts on homeostasis remain enigmatic. Here, we report the role of caspase-8 as a negative regulator of type-I IFN production during homeostasis in vitro and in vivo. Caspase-8 deficiency led to hyperactivation of basal type-I IFN signaling across multiple cell types and tissues and provided naturally heightened resistance to viral infection with norovirus. Mechanistically, the absence of caspase-8 allowed for an interaction between RIPK1 and TBK1, leading to enhanced TBK1 activation and aberrant type-I IFN production under homeostatic conditions. Loss of RIPK1 in caspase-8–deficient cells normalized TBK1 phosphorylation, IFN production and IFN signaling, thereby sensitizing cells to viral infection-induced inflammasome activation and inflammatory cell death, PANoptosis. In vivo, the elevated type-I IFN signaling, as well as the previously established early onset lymphadenopathy at 8 weeks of age, in caspase-8–deficient mice were reduced upon deletion of RIPK1 or type-I IFN neutralization. Overall, our study identified a mechanism which constrains tonic type-I IFN production and signaling during homeostasis. These results advance our understanding of tissue homeostasis and IFN regulation in infectious, autoimmune and autoinflammatory diseases, providing new insights for the development of disease treatments.

ORGANISM(S): Mus musculus

PROVIDER: GSE211623 | GEO | 2022/11/16

REPOSITORIES: GEO