Editors' ChoiceInflammation

Those Irritating Acellular Mitochondria

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Sci. Signal.  08 Dec 2009:
Vol. 2, Issue 100, pp. ec388
DOI: 10.1126/scisignal.2100ec388

Inflammation can be caused by infection or by noninfectious, or sterile, tissue damage. Iyer et al. found that cells killed by pressure disruption, complement-mediated lysis, or hypoxic conditions, but not by freezing and thawing or ultraviolet irradiation, triggered the release of interleukin-1β (IL-1β) from primed macrophages, indicative of an inflammatory response. IL-1β secretion required the NALP3 (Nacht domain–, leucine-rich repeat–, and PYD-containing protein 3) inflammasome and was abolished in cells deficient for components of this caspase-1–activating complex; caspase-1 is required for processing precursor IL-1β to the mature form. Exposure of primed macrophages to subcellular fractions from the pressure-disrupted cells showed that the mitochondrial fraction stimulated IL-1β secretion. Pretreatment of the isolated mitochondria or the disrupted cells with agents that decreased mitochondrial ATP content or production before their addition to the primed macrophages diminished the IL-1β secretion response. Endocytosis of the mitochondria by the macrophages was not required to stimulate IL-1β secretion, because inhibition of macrophage endocytosis with cytochalasin B or D did not eliminate the macrophage response. Instead, the purinergic receptor P2X7R appeared to be involved, because macrophages deficient in this receptor showed a substantially reduced IL-1β secretion response to pressure-disrupted cells, mitochondria, or complement-lysed cells. In vivo assays confirmed that intraperitoneal injection of pressure-disrupted cells or isolated mitochondria triggered neutrophil infiltration, and this response was reduced in P2X7R-deficient mice. Remarkably, mice deficient in components of the NALP3 inflammasome survived what would have been lethal renal ischemic injury in wild-type mice. Furthermore, the NALP3-deficient animals had less renal dysfunction and reduced neutrophil infiltration in response to nonlethal renal injury compared with the wild-type animals. Thus, limiting NALP3-mediated inflammation may prevent organ damage in response to tissue injury.

S. S. Iyer, W. P. Pulskens, J. J. Sadler, L. M. Butter, G. J. Teske, T. K. Ulland, S. C. Eisenbarth, S. Florquin, R. A. Flavell, J. C. Leemans, F. S. Sutterwala, Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc. Natl. Acad. Sci. U.S.A. 106, 20388–20393 (2009). [Abstract] [Full Text]

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