Research ArticleInflammation

γ-Secretase Limits the Inflammatory Response Through the Processing of LRP1

Sci. Signal.  25 Nov 2008:
Vol. 1, Issue 47, pp. ra15
DOI: 10.1126/scisignal.1164263

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Inflammatory responses, such as those elicited by bacterial lipopolysaccharide (LPS), are critical for clearance of infection, but these responses must then be reined in to prevent the occurrence of side effects such as tissue damage. Low-density lipoprotein receptor–related protein 1 (LRP1) is a multifunctional lipoprotein receptor that plays a role in endocytosis and signal transduction. Processing of LRP1 by the γ-secretase complex releases the intracellular domain (ICD) of LRP1 from the plasma membrane. Zurhove et al. now show that LPS-stimulated processing of LRP1 by γ-secretase results in ICD-mediated feedback inhibition of the inflammatory response, in part by inhibiting the activity of the transcription factor interferon regulatory factor 3. As well as linking γ-secretase and LRP1 to the innate immune response, these data are potentially of clinical relevance; the therapeutic use of γ-secretase inhibitors may have the undesirable outcome of shutting down a pathway that prevents uncontrollable inflammation.

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