Albumin internalizes and inhibits endosomal TLR signaling in leukocytes from patients with decompensated cirrhosis

Leukocyte endosomal trafficking plays a critical role in the anti-inflammatory actions of human albumin. Taking an immune look into decompensated cirrhosis In patients with acutely decompensated cirrhosis, human serum albumin (HSA) administration has been shown to reduce inflammation in patients; however, the mechanisms underlying treatment efficacy are unclear. Now, Casulleras et al. used peripheral blood leukocytes from patients and showed that HSA inhibited cytokine production induced by CpG-DNA. HSA was taken up by leukocytes and localized in endosomes, where it inhibited Toll-like receptor signaling. The results suggest that leukocytes play a critical role in the effect of HSA and offer an alternative perspective for understanding the pathophysiology of acutely decompensated cirrhosis. Human serum albumin (HSA) is an emerging treatment for preventing excessive systemic inflammation and organ failure(s) in patients with acutely decompensated (AD) cirrhosis. Here, we investigated the molecular mechanisms underlying the immunomodulatory properties of HSA. Administration of HSA to patients with AD cirrhosis with elevated circulating bacterial DNA rich in unmethylated cytosine-phosphate-guanine dideoxynucleotide motifs (CpG-DNA) was associated with reduced plasma cytokine concentrations. In isolated leukocytes, HSA abolished CpG-DNA–induced cytokine expression and release independently of its oncotic and scavenging properties. Similar anti-inflammatory effects were observed with recombinant human albumin. HSA exerted widespread changes on the immune cell transcriptome, specifically in genes related to cytokines and type I interferon responses. Our data revealed that HSA was taken up by leukocytes and internalized in vesicles positively stained with early endosome antigen 1 and colocalized with CpG-DNA in endosomes, where the latter binds to Toll-like receptor 9 (TLR9), its cognate receptor. Furthermore, HSA also inhibited polyinosinic:polycytidylic acid– and lipopolysaccharide-induced interferon regulatory factor 3 phosphorylation and TIR domain–containing adapter-inducing interferon-β–mediated responses, which are exclusive of endosomal TLR3 and TLR4 signaling, respectively. The immunomodulatory actions of HSA did not compromise leukocyte defensive mechanisms such as phagocytosis, efferocytosis, and intracellular reactive oxygen species production. The in vitro immunomodulatory effects of HSA were confirmed in vivo in analbuminemic humanized neonatal Fc receptor transgenic mice. These findings indicate that HSA internalizes in immune cells and modulates their responses through interaction with endosomal TLR signaling, thus providing a mechanism for the benefits of HSA infusions in patients with cirrhosis.