Peptidoglycans (PGNs) are pathogen-associated molecular patterns (PAMPs) that are shed by bacteria, including those of the microbiome, to stimulate an immune response. Uncontrolled immune stimulation can lead to chronic inflammation and shortened lifespan; hence, mechanisms exist to prevent excessive immune activation in response to PAMPs. New research in Drosophila demonstrates a role for nephrocytes in this regulatory process. “We show that nephrocytes remove microbiota-derived PGN fragments from the circulation to prevent aberrant immune activation,” explains Nicolas Buchon. “Thus, renal filtration of microbiota-derived PGN maintains immune homeostasis in Drosophila.”

Drosophila nephrocytes have molecular and functional similarities to podocytes and to cells of the reticuloendothelial system. To assess the role of nephrocytes and haemolymph (insect blood) filtration in immunity, Buchon and colleagues studied Drosophila with a mutation in Klf15 — the ortholog of human KLF15, which is required for podocyte differentiation — which lack nephrocytes. Despite the known ability of nephrocytes to detoxify hemolymph, Buchon and colleagues found that Klf15-null flies were more resistant to infection than wild-type flies. Further analyses showed that nephrocytes of wild-type flies removed PGN from the circulation via endocytosis and subsequent lysosomal degradation. This process was impaired in Klf15-null flies, resulting in excess PGN in haemolymph and constitutive activation of the Toll pathway. Despite their resistance to infection, Klf15-null flies had shorter lifespans than wild-type flies. This difference was, however, abolished by raising the flies under germ-free conditions, suggesting that the shortened lifespan of conventionally housed Klf15-null flies resulted from an aberrant immune response to microbiota.

The researchers propose that renal or reticuloendothelial systems could have similar immunoregulatory functions in mammals. “Renal filtration could regulate the levels of microbiota-derived PAMPs, such as PGN, in the blood, to maintain immune homeostasis,” says Buchon. “Thus impairment of renal function could directly induce chronic immune activation with proinflammatory effects.”