A fundamental question is whether and how activation of innate immune responses triggers pathogen-specific adaptive immune responses. Most of the studies looking at the link between the two immune branches have focused on responses downstream the activation of innate immune receptors called Toll-like receptors (TLRs). Studies exploring adaptive immune responses after inflammasome, another family of innate immune sensors, activation have been conducted in the presence of TLR ligands. Consequently, we still lack the knowledge if inflammasomes activation is sufficient to induce immunity and inflammation in vivo. In this proposal, we seek to test the hypothesis that cell-type-specific activation of the inflammasome is sufficient to induce inflammation and adaptive immune responses in vivo. Understanding in vivo effects of inflammasome activation in specific cell types as well as systemic activation is important because little work has been done to selectively activate the inflammasome in vivo. Most work to understand inflammasome effects has been done in the context of pathogen infections, which stimulates other innate immune sensors. Pursuing a comprehensive study of the adaptive responses downstream of selective inflammasome activation will further the field's understanding of the connection between the innate immune response and stimulation of an adaptive immune response. This could potentially open up more research into the adjuvancy of inflammasomes. Using inducible expression knock-in mice we generated, flow cytometry, and cytokine assays, we will determine if cytosolic flagellin is sufficient to activate the inflammasome and induce inflammation in vivo (Aim 1). To determine the signaling events downstream of NLRC4 inflammasome activation in specific cell populations, we will continue to use the same flow cytometry and cytokine assays but in cell-specific expression knock-in mice (Aim 2). Lastly, we will define the adaptive immune responses downstream of selective NLRC4 inflammasome activation using our inducible expression knock-in mice, flow cytometry, and B and T cell assays (Aim 3).
Inflammasomes, the innate immune sensor family, were only recently described in 1999; therefore, much is still unknown about downstream effects of inflammasome activation in vivo. To fill in the gaps of our knowledge it is crucial to determine if inflammasome activation alone is sufficient to stimulate inflammation and what, if any, adaptive immune response.
| Nichols, Randilea D; von Moltke, Jakob; Vance, Russell E (2017) NAIP/NLRC4 inflammasome activation in MRP8+ cells is sufficient to cause systemic inflammatory disease. Nat Commun 8:2209 |
