This is supported by findings that IL-1β secretion in response to necrotic cells
is not completely abrogated in P2X7R-deficient macrophages and dendritic cells 22, 37. We also found that unlike NLRP3−/− mice, P2X7R−/− mice retain a neutrophilic influx when challenged intraperitoneally with pressure-disrupted necrotic cells suggesting an NLRP3-dependent inflammatory response independent of P2X7R 22. In contrast, however, oxaliplatin-treated tumor cells failed to prime T cells for IFN-γ production in P2X7R−/− mice 37. In addition, tumors in P2X7R−/− mice were less responsive to oxaliplatin compared Selleck GSK1120212 to WT mice. The reason for the discrepancy for the in vivo requirement of the P2X7R−/− in these two studies is unclear. It is possible that, although the immunogenicity
of necrotic cells is predominantly dependent on the P2X7R, the residual IL-1β that is made in the absence of the P2X7R in response to necrotic cells Selleck BGJ398 is sufficient to induce neutrophil infiltration to the site of injury. The nature of these factors from necrotic cells that activate NLRP3 independently of the P2X7R remain to be elucidated; action through other purinergic receptors is one strong possibility. It is established that activation of the NLRP3 inflammasome is a two-step process with the initial priming step delivered by NF-κB activation, which also drives pro-IL-1β generation (reviewed in 33). Generally, in vitro studies have provided priming via microbial products acting on TLR. The initial priming step in vivo has been unclear especially for non-microbial activators of the NLRP3 inflammasome. The recent studies by Iyer et al. 22 and Ghiringhelli et al. 37 show that endogenous DAMP released concomitantly with cellular injury prime macrophages and
dendritic cells for inflammasome activation. This functionality was confirmed by in vitro studies wherein HMGB-1, biglycan and hyaluronic acid were each capable of priming NLRP3 inflammasome activation in Uroporphyrinogen III synthase response to necrotic cells. The in vivo significance of these studies is underlined as both biglycan and hyaluronic acid expression are upregulated following renal ischemia-reperfusion injury. Consistent with this is the finding that mice deficient in either TLR2 or TLR4, the receptors through which biglycan and hyaluronic acid can activate macrophages 40, 41, have improved outcomes following renal ischemia-reperfusion injury 42–44. Mice deficient in another cellular receptor for hyaluronic acid, CD44, also display reduced renal injury following ischemia-reperfusion injury 45. In addition to their role in priming for inflammasome activation, biglycan and hyaluronic acid have themselves been shown to activate the NLRP3 inflammasome.