A tissue injury repair pathway distinct but parallel to host pathogen defense

Abstract

Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces interferons (IFNs) to activate resistance mechanisms. Applying unbiased phylogenetic analysis, we show that interleukin-24 (IL24) is among the closest evolutionary homologs to the IFN family and shares a common ancestral origin. However, in contrast to IFNs, IL24 induction occurs specifically in barrier epithelial progenitors after injury and is independent of microbiome or adaptive immunity. Surprisingly, Il24 ablation impedes not only epidermal proliferation and re-epithelialization, but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic Il24 induction in homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, sustained Il24 expression depends upon both IL24 receptor/STAT3 signaling and also hypoxia-stabilized HIF1α, which converge following injury. Thus, parallel to the IFN-mediated innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL24-mediated tissue repair.

Alcaligenes faecalis corrects aberrant matrix metalloproteinase expression to promote reepithelialization of diabetic wounds

“…As such, they are equipped with myriad receptors that detect bacterial products. There is growing appreciation for injury signals, beyond pathogen-and damage-associated molecular patterns (73), that are detected by keratinocytes and can induce reepithelialization (74). It is reasonable to hypothesize that an A. faecalis-derived peptide is sensed by keratinocyte receptors and induces a promigratory phenotype, although the identity of that signal will need to be identified in future studies.…”

Systematic dissection of tumor-normal single-cell ecosystems across a thousand tumors of 30 cancer types

“…Therefore, targeting the AKR1C1 + inflammatory fibroblast might offer new therapeutic insights, especially in OV and UCEC. Intriguingly, WNT5A + inflammatory fibroblast has been shown to interact with diverse TME components configuring inflammatory and pro-tumorigenic milieu via WNT5A, GREM1, and IL24 41,[44][45][46] . Future studies that therapeutically target WNT5A + inflammatory fibroblasts should be pursued to mitigate deleterious consequences associated with these protumorigenic fibroblasts.…”

“…S12E). Furthermore, WNT5A + inflammatory fibroblast showed strong interactions with fibroblast populations including desmoplastic fibroblasts (WNT5A:PTK7, WNT5A:ROR2, and GREM1:ACVR1), with themselves in homotypic interactions (WNT5A:PTK7 and GRE-M1:ACVR1), and BMP4 + fibroblasts (GREM1:ACVR1) to mimic wound repair process to potentiate mesenchymal proliferation and migratory phenotype of cells through both autocrine and paracrine mechanism 41,42 (Fig. 4D and Supplementary Fig.…”

“…Proangiogenic and proinflammatory engagement of GREM1 from WNT5A + inflammatory fibroblast and ACVRL1 from endothelial cells were also recognized 43 . Collectively, WNT5A + inflammatory fibroblasts secrete diverse ligands such as WNT5A, GREM1, and IL24, that potentiate proliferation, migration, and survival in numerous contexts, including tissue regeneration, inflammation, and cancer 41,[44][45][46] . They interact with diverse cellular components such as cancer cells, fibroblasts, and endothelial cells to ultimately shape the pro-tumorigenic and core inflammatory TME.…”

Inhibitory effect of human interleukin-24 on the proliferation, migration, and invasion of cervical cancer cells

“…12–14 Human interleukin-24 (hIL-24) is notable for its wide range of biological actions, including its tumor-suppressing effects in various cancer forms. 15–17 Although research has shown the ability of hIL-24 to inhibit tumor cell growth and promote apoptosis, its use in treating cervical cancer is not well explored. 18–20…”