Using peripheral blood samples from healthy donors and cirrhotic patients, we identified that classical monocytes, which are the most abundant cell population in the blood, are the most efficient cells in albumin up-take. Of interest, during systemic inflammation, classical monocytes are crucial players in the production of pro-inflammatory mediators.

By co-immunoprecipitations and mass-spectrometry analysis of immunoprecipitated material, we identified the neonatal Fc receptor (FcRn) and CD44 as potential albumin receptors in classical monocytes. Whether CD44 serves as an albumin receptor remains to be investigated. However, FcRn depletion by lentiviral shRNA confirmed that in the absence of FcRn, classical monocyte ability to store the albumin is decreased. Finally, by cell biology methods, such as protein depletion via shRNA, confocal microscopy and flow cytometry, we identified that after internalization, the albumin is first targeted to early endosomes and arrive in lysosomes, a cellular compartment from where endosomal Toll-like receptors trigger the inflammatory response. The endocytic pathway by which albumin is internalized in early endosomes is clathrin-independent and involves dynamin-2, ARF1 and ARF6.