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For a long time, Toll-like Receptor 4 (TLR4) was recognized as the only receptor that recognizes lipopolysaccharide (LPS) to instruct the activation of the immune system. CD14 was believed to act only by enhancing the recognition of LPS by TLR4, and by favoring TLR4-dependent transcriptional responses. We contradicted the prevailing dogma by showing that the response of phagocytes to bacterial LPS does not necessarily depend on TLR4, and that the CD14 alternative pathway controls the bacteria-induced endocytosis of TLR4, a process that is critical for the signaling functions of this receptor (Cell, 2011). We also demonstrated that, in response to LPS, CD14 activates the transcription factors NFAT. We found that NFAT regulates cell survival and PGE2 production in dendritic cells (Nature, 2009; The Journal of Clinical Investigation, 2012). Overall, these investigations have uncovered a new LPS response pathway that operates in numerous mammalian cell types independently of TLR4. These very novel findings proved to be prescient, spawning a large number of subsequent studies that have highlighted additional TLR4-independent responses to LPS. 

Currently, we are investigating how CD14 modulates the inflammatory response by binding to exogenous as well as endogenous inflammatory mediators.


Inflammasome activation in dendritic cells. Credit to Dr. Di Gioia

Header picture: NETosis. Credit to Dr. Poli

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