Tissue-autonomous immune response regulates stress signaling during hypertrophy

Abstract

Postmitotic tissues are incapable of replacing damaged cells through proliferation, but need to rely on buffering mechanisms to prevent tissue disintegration. By constitutively activating the Ras/MAPK-pathway via RasV12-overexpression in the postmitotic salivary glands of Drosophila larvae, we overrode the glands adaptability to growth signals and induced hypertrophy. The accompanied loss of tissue integrity, recognition by cellular immunity and cell death are all buffered by blocking stress signalling through a genuine tissue-autonomous immune response. This novel, spatio-temporally tightly regulated mechanism relies on the inhibition of a feedback-loop in the JNK-pathway by the immune effector and antimicrobial peptide Drosomycin. While this interaction might allow growing salivary glands to cope with temporary stress, continuous Drosomycin expression in RasV12-glands favors unrestricted hypertrophy. These findings indicate the necessity to refine therapeutic approaches that stimulate immune responses by acknowledging their possible, detrimental effects in damaged or stressed tissues.

Anti-Fibrotic Activity of an Antimicrobial Peptide in a <b><i>Drosophila</i></b> Model

“…w 1118 ,Beadex MS1096 -Gal4 (Referred here as Bx : 8860/Bl), w 1118 , w 1118 ;;UAS-Ras V12 (4847/Bl), w 1118 ;;UAS-Drs ( Drs-OE : overexpression [46], w 1118 ; Vkg G00454 /CyO.GFP [48] , UAS-Drs-HA [49], Bx,mCD8::RFP [46] and Sgs3-GFP (5884/Bl) (see also online suppl. Table 1; for all online suppl.…”

“…Female virgins were collected for 5 days and crossed to the respective male on day 7. Progeny larvae were grown as described in Ref [46]. Ten to twenty salivary gland pairs were fixed in 4% PFA for 20 min.…”

“…RNA extraction, cDNA synthesis, and qPCR analysis were performed as described in Ref [46]. qPCR was performed on 3 independent replicas targeting Rpl32 , Sgs3, and Eig73Ee .…”

“…In contrast, the proximal part of SGs displays an almost normal histology despite strong activation of AMPs, most notably the AMP Drs. Due to the similarities to fibrotic lesions in mammals, we refer to the regions with dysregulated ECM deposition concomitant with inflammatory reactions [46] as fibrotic deposits, although we acknowledge some differences to mammalian fibrosis [47]. Surprisingly, forced SG-wide expression of Drs, including distal SGs, strongly reverted fibrosis and restored tissue integrity in distal SGs and secretory activity to almost normal levels.…”

Cecropins contribute toDrosophilahost defence against fungal and Gram-negative bacterial infection

“…Drosophila AMPs also regulate the gut microbiota downstream of the Imd pathway, a function consistent with their bactericidal activity (Marra et al 2021). However, recent studies have suggested that AMP-like genes may play more subtle roles in other processes like memory formation (Barajas-Azpeleta et al 2018), an erect wing response upon infection (Hanson et al 2021), tumor control (Parvy et al 2019;Araki et al 2019), or regulation of JNK signaling in the salivary gland (Krautz et al 2020). While we confirm a primary importance for Cecropins and other AMPs in the systemic immune response, exploring the functions of AMPs including Cecropins in non-canonical roles is an exciting future direction of research.…”