Getting closer to the dirty little secret

Abstract

The molecular mechanism behind alum adjuvanticity is probably the oldest secret of immunology. In this issue of Immunity, Kuroda et al. (2011) and Kool et al. (2011) identify NLRP3 inflammasome-independent signaling to be crucial for the Th2 cell response induced by aluminum salts.

Figure 1. Mechanisms of particulate induced immunity - an updated model

Upon phagocytosis, particulates like aluminium salts or monosodium urate crystals (MSU) cause lysosomal damage. This initiates at least two separate signaling pathways: First, the activation of the NLRP3 inflammasome due to the release of enzymes like cathepsin B into the cytoplasm. Autocatalytically activated caspase-1 mediates the proteolytic cleavage of pro-IL-1β in biologically active IL-1β, accounting for the inflammatory response to particulates. Second, the activation of Syk, which in turn activates cytosolic phospholipase A2 (cPLA2), probably via p38 MAP kinase resulting in the release of arachidonic acid from membrane lipids. Cyclooxygenase-2 (COX2) and membrane associated PGE synthase-1 (mPGES-1) convert arachidonic acid to prostaglandin E2 (PGE2).