Regenerative Inflammation: Lessons from Drosophila Intestinal Epithelium in Health and Disease

Abstract

Intestinal inflammation is widely recognized as a pivotal player in health and disease. Defined cytologically as the infiltration of leukocytes in the lamina propria layer of the intestine, it can damage the epithelium and, on a chronic basis, induce inflammatory bowel disease and potentially cancer. The current view thus dictates that blood cell infiltration is the instigator of intestinal inflammation and tumor-promoting inflammation. This is based partially on work in humans and mice showing that intestinal damage during microbially mediated inflammation activates phagocytic cells and lymphocytes that secrete inflammatory signals promoting tissue damage and tumorigenesis. Nevertheless, extensive parallel work in the Drosophila midgut shows that intestinal epithelium damage induces inflammatory signals and growth factors acting mainly in a paracrine manner to induce intestinal stem cell proliferation and tumor formation when genetically predisposed. This is accomplished without any apparent need to involve Drosophila hemocytes. Therefore, recent work on Drosophila host defense to infection by expanding its main focus on systemic immunity signaling pathways to include the study of organ homeostasis in health and disease shapes a new notion that epithelially emanating cytokines and growth factors can directly act on the intestinal stem cell niche to promote “regenerative inflammation” and potentially cancer.

Inflammation Shapes Stem Cells and Stemness during Infection and Beyond

“…The ability of gut stem cells to respond directly to patterns, such as LPS (via TLR4) and peptidoglycan (via Nod2), may underlie mechanisms of tissue response not only to pathogenic bacteria but also commensals and is likely important to general tissue homeostasis via the interaction with intestinal microbiota. The findings in mammalian systems are corroborated by extensive literature in other experimental systems, such as Drosophila (Panayidou and Apidianakis, 2013). …”

Reparative inflammation takes charge of tissue regeneration

“…Self-resolving inflammation is the first stage of wound repair and is followed by tissue formation and eventual remodelling 15 . Although not as extensively studied as its innate immune or antimicrobial functions, the regenerative function of inflammation is evolutionarily conserved and has been amply documented in the fruit fly Drosophila , in which genetic analysis has highlighted its role in regeneration of adult tissues such as the injured midgut 16 and in closure of larval wounds 17 .…”

“…In innate immunity, these pathways are important for the induction of antimicrobial peptides in haemocytes, the fat body and the midgut — the fly equivalents of myeloid cells, the liver and the mammalian intestine, respectively. The same pathways also control regeneration and wound healing by stimulating proliferation of ISCs and ASCs, and modulating their differentiation 16 . Reactive oxygen species (ROS) produced during tissue injury and infection are an important cue that couples inflammation to ISC proliferation through activation of Jun N-terminal kinases (JNKs) and the antioxidant transcription factor and NRF2 homologue CncC 19 .…”

Ectopic tissue engineered ligament with silk collagen scaffold for ACL regeneration: A preliminary study

“…Amongst these, macrophages have been intensively studied and are thought to be one of the most important cell types involved in this process, because it can produce and secrete various bioactive molecules, including vascular endothelial growth factor (VEGF), transforming growth factor-beta (TGF-b), basic fibroblast growth factor (bFGF), platelet derived growth factor-BB (PDGF-BB), tumor necrosis factor (TNF), and various cytokines of the Interleukin (IL) family such as IL-6, IL-10 and IL-17 [34][35][36][37]. These factors play critical roles in controlling neovascularization and vascular remodeling, as well as the regenerative response by promoting tissue-endogenous adult stem cell proliferation [37,38]. Depletion of macrophages have been proven to be detrimental to vascular formation and wound healing [39,40].…”