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 method 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, Inhibitors,Modulators,Libraries 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 that notion, at least in bone tissues. The difference between professional and nonprofes sional phagocytes Inhibitors,Modulators,Libraries relies on, at least in part, their rap idity and efficiency of phagocytosis. Although neutrophils rapidly ingest MSU in vitro, only a few neutrophils are shown with intracellular microcrystals, and these neutrophils rapidly die with release of cel lular content. Macrophages Inhibitors,Modulators,Libraries poorly ingest MSU microcrystals that have, however, profound stimula tory effects on these phagocytes. In contrast, most of the OBs that slowly vacuolize microcrystals, ingested MSU but did not die from this process.
Moreover, OBs in contact with MSU crystals rapidly stimulate signaling of phagocytosis and NLRP3 for their subsequent Inhibitors,Modulators,Libraries autophagy, both mechanisms of particle destruction that fail in MSU degradation. fairly OBs with MSU crystals inside did not die, but showed pro found changes of their functions, becoming bone cells that have reduced capacity of mineralization, that degrade the calcified matrix, but that have no change of RANKL and OPG mRNAs. Also, the upregulation of autophagy by NLRP3 in these conditions did not generate IL 1B, although mammalian cells can produce IL 1B via an autophagy based secretory pathway.