Pyrin Levels in Human Monocytes and Monocyte-Derived Macrophages Regulate IL-1β Processing and Release

Abstract

Macrophages and their precursors, monocytes, are key cells involved in the innate immune response. Although both monocytes and macrophages produce caspase-1, the key enzyme responsible for pro-IL-1β processing; macrophages are limited in their ability to activate the enzyme and release functional IL-1β. In this context, because mutations in the pyrin gene (MEFV) cause the inflammatory disorder familial Mediterranean fever, pyrin is believed to regulate IL-1β processing. To determine whether variations in pyrin expression explain the difference between monocytes and macrophages in IL-1β processing and release, pyrin was studied in human monocytes and monocyte-derived macrophages. Although monocytes express pyrin mRNA and protein, which is readily inducible by endotoxin, monocyte-derived macrophages express significantly less pyrin mRNA and protein. Pyrin levels directly correlated with IL-1β processing in monocytes and macrophages; therefore, we asked whether pyrin might promote IL-1β processing and release. HEK293 cells were transfected with pyrin, caspase-1, apoptotic speck protein with a caspase recruitment domain, and IL-1β. Pyrin induced IL-1β processing and release in a dose-dependent manner. Conversely, pyrin small interference RNA suppressed pro-IL-1β processing in both THP-1 cells and fresh human monocytes. In summary, both pyrin expression and IL-1β processing and release are diminished upon the maturation of monocytes to macrophages. When pyrin is ectopically expressed or silenced, IL-1β processing and release parallels the level of pyrin. In conclusion, in the context of endotoxin-induced activation of mononuclear phagocytes, pyrin augments IL-1β processing and release.

The spectrum of autoinflammatory diseases: recent bench to bedside observations

“…In an in-vitro transfection model, wildtype pyrin acts as a proinflammatory molecule via the formation of a pyrin inflammasome complex [19]. A recent publication [20] is in keeping with this postulated pro-inflammatory role of pyrin, as it demonstrates that as monocytes differentiate into macrophages, pyrin protein expression diminishes with a parallel reduction in levels of IL-1β. All the above studies have been generated using in-vitro or murine models of disease, and the results may be explained by the changing role of pyrin depending on its cellular context.…”

COPs and POPs: Modulators of Inflammasome Activity

“…Although pyrin does not share common domain architecture with NLRs, it has been shown to interact with ASC to form caspase-1-activating inflammasomes (37)(38)(39)(40). However, contrary to being an inflammasome activator, pyrin has also been suggested to function as a negative regulator of inflammasomes, because targeted disruption of pyrin in mice resulted in enhanced secretion of IL-1␤ (41).…”

Evasion of inflammasome activation by microbial pathogens

“…Recently, NLRP2, NLRP6, NLRP7, RIG-I, pyrin, and IFI16 have been implicated in the formation of unique inflammasome complexes (4)(5)(6)(7)(8); however, additional investigation will be required to establish their precise roles in inflammasome formation and activation. Pyrin, mutations in which cause the autoinflammatory disease familial Mediterranean fever, can also form a caspase-1-activating inflammasome in concert with ASC (9,10). Interestingly, a recent study demonstrated that the Pyrin inflammasome is activated through the sensing of bacterial modification and inactivation of Rho GTPases (11).…”