Stress granule component TIA-1 is a negative regulator of the non-canonical NLRP3 inflammasome

Abstract Inflammasomes are cytosolic signaling hubs assembled upon pathogen- or damage associated molecular patterns (PAMP and DAMP) sensing by innate immune pattern recognition receptors (PRR). Lipopolysaccharide (LPS) present on the cell wall of gram-negative bacteria is a PAMP that activates caspase 11 (CASP11) dependent nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome (known as non-canonical NLRP3 inflammasome) leading to pyroptosis. Several host factors are shown to promote non-canonical NLRP3 inflammasome activation by making LPS readily available for recognition by CASP11. Here, we report T-cell intracellular antigen-1 (TIA1), an RNA binding protein as a negative regulator of non-canonical NLRP3 inflammasome. Using bone marrow-derived macrophages (BMDMs), we demonstrated that the loss of TIA1 led to an increase in caspase-1 (CASP1) activity in response to cytosolic LPS. A previous study had demonstrated that mice lacking Tia1 are more susceptible to LPS mediated endotoxic shock. Our results provide a potential explanation for this observation by showing loss of TIA1 increases non-canonical NLRP3 inflammasome activation resulting in increased inflammation and pathogenesis during LPS mediated endotoxic shock. Further, TIA1 mediated inhibition of non-canonical NLRP3 inflammasome is independent of TIA1’s regulatory role in gene transcription as well as its role in stress granule assembly. TIA1 is also dispensable for activation of the canonical NLRP3 inflammasome as well as AIM2 and NLRC4 inflammasomes. While, the exact mechanism by which TIA1 inhibits non-canonical inflammasome activation remains to be elucidated, our finding that TIA1 is a negative regulator indicates the presence of undiscovered regulatory mechanisms. Future studies will focus on unraveling these mechanisms for developing anti-inflammatory drugs that exploit non-canonical inflammasome activity modulation.