PGRP-SC2 Promotes Gut Immune Homeostasis to Limit Commensal Dysbiosis and Extend Lifespan

Abstract

Summary Interactions between commensals and the host impact the metabolic and immune status of metazoans. Their deregulation is associated with age-related pathologies like chronic inflammation and cancer, especially in barrier epithelia. Maintaining a healthy commensal population by preserving innate immune homeostasis in such epithelia thus promises to promote health and longevity. Here we show that in the aging intestine of Drosophila, chronic activation of the transcription factor Foxo reduces expression of Peptidoglycan Recognition Protein SC2 (PGRP-SC2), a negative regulator of IMD/Relish innate immune signaling, and homologue of the anti-inflammatory molecules PGLYRP1-4. This repression causes deregulation of Rel/NFkB activity, resulting in commensal dysbiosis, stem cell hyperproliferation, and epithelial dysplasia. Restoring PGRP-SC2 expression in enterocytes of the intestinal epithelium, in turn, prevents dysbiosis, promotes tissue homeostasis and extends lifespan. Our results highlight the importance of commensal control for lifespan of metazoans, and identify SC-class PGRPs as longevity-promoting factors.

Molecular and functional characterization of peptidoglycan-recognition protein SC2 (PGRP-SC2) from Nile tilapia (Oreochromis niloticus) involved in the immune response to Streptococcus agalactiae

“…To understand the immune system and immune response against infection is useful for enhancing the immunity of cultured fish, which now becomes more and more important in aquatic research [32e34]. PGRP-SC2, the member of PGRP family, plays an important role in regulation of innate immune response [23,24]. However, in teleosts, PGRP-SC2 has only been cloned from tongue sole (Cynoglossus semilaevis) [25], and no information is available to date about PGRP-SC2 in Nile tilapia.…”

“…PGLYRP-2 is homologous to mammal PGLYRP-2, while PGLYRP-5 and PGLYRP-6 are only found in teleost. However, the PGRP homolog of the SC2 type (PGRP-SC2), which was firstly discovered in fruit fly and proved to play an important role in regulation of innate immune response [23,24], has been reported only in tongue sole (Cynoglossus semilaevis) [25], and the study of fish PGRP-SC2 expression profiles and functional properties is rather limited.…”

Anti‐inflammaging effects of human alpha‐1 antitrypsin

“…The importance of Relish in controlling inflammaging associated with neurodegenerative diseases has been documented before (Kounatidis et al ., 2017). It has also been shown that inhibiting the IMD/Relish pathway in old intestine enterocytes prevented dysbiosis, reduced dysplasia, and extended the lifespan (Guo et al ., 2014). An extensive QTL mapping study found that the chromosomal interval containing Relish has the strongest impact on lifespan of Drosophila (Highfill et al ., 2016).…”

“…DNA damage response and its downstream GATA4, p38MAPK, and mTOR pathways regulate SASP (Rodier et al ., 2009; Freund et al ., 2011; Kang et al ., 2015; Laberge et al ., 2015). All of these pathways converge on NF‐ĸB, the master transcription regulator that controls the expression of immune‐responsive genes (Zhang et al ., 2013; Guo et al ., 2014). A recent study showed SASP gene expression required cGMP‐AMP (cGAMP) synthase (cGAS) in mouse and human senescence model in vitro induced by DNA damage and ionizing radiation (Yang et al ., 2017).…”

“…Major regulatory pathways in innate immunity are highly conserved between Drosophila and vertebrates (Buchon et al ., 2014). As a result, it is widely used as a model in aging‐related immune regulation studies (Guo et al ., 2014) and has led to many seminal findings in this field. The Gal4‐UAS system with tissue‐specific promoter can provide robust spatial and temporal control of transgene expression.…”