It is also important to stress that NLRP3 activated by MSU in OBs does not engage the inflammasome signaling path ways, as it does in professional phagocytes, because expression of selleck chem Wortmannin the adaptor ASC was not increased, and no activation of caspase 1 was detected in MSU stimulated OBs. Our Inhibitors,Modulators,Libraries results demonstrate that NLRP3 has an inflammasome independent, cell intrinsic effect in OBs ingesting MSU microcrystals. MSU interaction with OBs also seems particularly ori ginal at the level of kinetics and regulation of phagocyt osis. First, engulfment of MSU by OBs is related to a process of phagocytosis, because cytochalasin D blocked entirely MSU internalization, whereas colchicine, an in hibitor of microtubule polymerization, had no effect.
OBs can ingest various foreign particles like MSU, titan ium, Inhibitors,Modulators,Libraries latex beads, or microorganisms like Escherichia coli or Candida albicans. However, Ti, for in stance, activates NFB in OBs, whereas MSU did not. Inhibitors,Modulators,Libraries Moreover, this difference of signals involved in MSU phagocytosis is also demonstrated at the level of Src kinases required for phagocytosis by professional phagocytes, whereas they are not required by OBs. In addition, ERK1 2 and p38 MAPK, which positively regulate conventional phagocytosis, have opposite ef fects in MSU activated OBs as human phosphokinase array revealed a phosphorylation of p38 MAPK, but SB203580, an inhibitor of p38, did not reduce but fa cilitated phagocytosis. Our results suggest that phago cytic stimulation by MSU required ERK activation but not p38, which seems to act as a repressor of MSU phago cytosis by OBs.
Such antagonistic roles of ERK1 2 and p38 MAPK are reminiscent of another condition in which Inhibitors,Modulators,Libraries ERK1 2 and p38 MAPK differentially regulate heme bio synthesis. The primary function of both phagocytosis and au tophagy is to maintain cellular homeostasis by degrading foreign particles that can represent successively an extra cellular danger and, after their ingestion, another intra cellular danger, if phagocytosis failed in its function of destruction. Interestingly, even if extracellular MSU crystals present a major proinflammatory potential, they have been recognized as an endogenous danger signal useful to immunity. From the presence of such MSU crystals in cells and tissues emerges the concept of their degradation. It is well known that an attack of gout can spontaneously improve and MSU crystals remain present in joints and tissues.
MSU deposits can be shown in vari ous tissues from the joint to cartilage, bone, vasculature, skin, and kidney. It seems that once crystallized in humans, MSU cannot be easily and spontaneously de graded. Our results seem to confirm Inhibitors,Modulators,Libraries that notion, at least in bone tissues. The difference between professional and nonprofes sional phagocytes may relies on, at least in part, their rap idity and efficiency of phagocytosis.