Understanding the complex role of exosomes in intestinal ischemia-reperfusion injury: from pathogenesis to protection

Abstract

Extracellular vesicles, which are predominantly classified into ectosomes and exosomes, are released by all cells under both physiological conditions and in response to acquired pathological states. Exosomes demonstrate multifaceted functions: they regulate cellular homeostasis through the elimination of redundant or detrimental intracellular components, function as mediators in intercellular signaling pathways, and serve as potential vectors for both diagnostic and therapeutic applications. Intestinal ischemia-reperfusion injury (IRI), a prevalent form of tissue and organ injury in surgical settings, has been extensively investigated. Emerging evidence indicates a crucial relationship between exosomes and intestinal IRI, specifically regarding how exosomes derived from either intestinal tissue or distant organs can modulate the pathophysiological progression of intestinal IRI. This review systematically evaluates the mechanistic roles of exosomes in intestinal IRI and their involvement in post-intestinal IRI multiple organ dysfunction, aiming to establish a theoretical foundation for therapeutic interventions and future research directions.

Keywords: exosomes; intestinal injury; intestinal ischemia-reperfusion injury; ischemia-reperfusion injury; multiorgan injury.

FIGURE 1

Schematic illustration of exosome biogenesis. Exosome formation encompasses a series of highly orchestrated cellular processes. The initial step involves plasma membrane invagination, forming characteristic cup-shaped structures that incorporate cell surface proteins and their associated soluble components. These structures are essential for early sorting endosome development, a process regulated by both the Golgi apparatus and endoplasmic reticulum. The maturation process continues as early endosomes progress to late sorting endosomes under the precise control of the endosomal sorting complex required for transport machinery and associated transport proteins. Subsequently, secondary invagination occurs, leading to the formation of multivesicular bodies (MVBs). These specialized compartments serve as repositories for diverse bioactive molecules, which are ultimately released into the extracellular space through MVB-plasma membrane fusion events, facilitating intercellular communication and molecular exchange.

FIGURE 2

Intestine-derived exosome-mediated signaling cascades in remote organ injury following intestinal IRI. During intestinal IRI, damage-associated exosomes, predominantly released by intestinal epithelial cells, enter systemic circulation and subsequently accumulate in distant organs. These exosomes trigger multi-organ dysfunction through distinct molecular pathways: in the liver, they activate resident macrophages; in the brain, they induce microglial activation and neuronal injury. Paradoxically, these same exosomes demonstrate protective effects through MAP4K4 and Gprc5a signaling pathways, potentially serving as endogenous modulators of intestinal IRI severity.

FIGURE 3

Therapeutic mechanisms of non-intestinal exosomes in intestinal IRI. Exosomes derived from multiple sources - human umbilical cord mesenchymal stem cells, human breast milk, and mesenteric lymph nodes - exhibit protective effects against intestinal IRI through distinct molecular mechanisms. These mechanisms include: (1) activation of the PTEN/Akt/Nrf2 signaling axis, (2) modulation of the TLR4/MyD88/NF-κB inflammatory cascade, and (3) METTL3-dependent pathways. Together, these mechanisms contribute to reduced intestinal cell damage and enhanced barrier function restoration, ultimately attenuating intestinal IRI.