TNFα promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium

Birkl, Dorothee; Quirós, Miguel; García-Hernández, Vicky; Zhou, Dennis W.; Brazil, Jennifer C.; Hilgarth, Roland S.; Keeney, Justin; Yulis, Mark; Bruewer, Matthias; Garcı́a, Andrés J.; Leary, Monique N O; Parkos, Charles A.; Nusrat, Asma

doi:10.1038/s41385-019-0150-8

Cited by 40 publications

(33 citation statements)

References 48 publications

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“…Active and coordinated repair responses that promote epithelial cell migration and proliferation are necessary to reestablish mucosal barrier function and intestinal homeostasis (14). We and others have shown that regulated spatiotemporal recruitment of leukocytes that interact with the repairing epithelium plays an important role in ensuring timely mucosal repair (15)(16)(17). SPMs have been demonstrated to have important roles in orchestrating resolution of inflammation in different tissues by triggering anti-inflammatory and proresolution responses in immune cells (18).…”

Section: Discussionmentioning

confidence: 99%

Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing

Quirós

Feier

Birkl

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Resolution of intestinal inflammation and wound repair are active processes that mediate epithelial healing at mucosal surfaces. Lipid molecules referred to as specialized proresolving mediators (SPMs) play an important role in the restorative response. Resolvin E1 (RvE1), a SPM derived from omega-3 fatty acids, has been reported to dampen intestinal inflammation by promoting anti-inflammatory responses including increased neutrophil spherocytosis and macrophage production of IL-10. Despite these observations, a role for RvE1 in regulating intestinal epithelial cell migration and proliferation during mucosal wound repair has not been explored. Using an endoscopic biopsy-based wound healing model, we report that RvE1 is locally produced in response to intestinal mucosal injury. Exposure of intestinal epithelial cells to RvE1 promoted wound repair by increasing cellular proliferation and migration through activation of signaling pathways including CREB, mTOR, and Src-FAK. Additionally, RvE1-triggered activation of the small GTPase Rac1 led to increased intracellular reactive oxygen species (ROS) production, cell–matrix adhesion, and cellular protrusions at the leading edge of migrating cells. Furthermore, in situ administration of RvE1-encapsulated synthetic targeted polymeric nanoparticles into intestinal wounds promoted mucosal repair. Together, these findings demonstrate that RvE1 functions as a prorepair lipid mediator by increasing intestinal epithelial cell migration and proliferation, and highlight potential therapeutic applications for this SPM to promote mucosal healing in the intestine.

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Section: Discussionmentioning

confidence: 99%

Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing

Quirós

Feier

Birkl

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…PAF mediates a wide variety of cellular functions and cell–cell interactions. Therefore, PAF is involved in several physiological processes including apoptosis, physiological inflammation, wound healing, reproduction, angiogenesis, long-term potentiation, and potentially retrograde signalling [4,5,6,7]. However, PAF is also a potent pro-inflammatory mediator that is implicated in a variety of conditions and chronic diseases such as cancer, renal diseases, cerebrovascular and central nervous system disorders, allergies, asthma, infections, and cardiovascular diseases (CVD) [5,8,9,10,11,12,13].…”

Section: Platelet-activating Factormentioning

confidence: 99%

Forty Years Since the Structural Elucidation of Platelet-Activating Factor (PAF): Historical, Current, and Future Research Perspectives

2019

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In the late 1960s, Barbaro and Zvaifler described a substance that caused antigen induced histamine release from rabbit platelets producing antibodies in passive cutaneous anaphylaxis. Henson described a ‘soluble factor’ released from leukocytes that induced vasoactive amine release in platelets. Later observations by Siraganuan and Osler observed the existence of a diluted substance that had the capacity to cause platelet activation. In 1972, the term platelet-activating factor (PAF) was coined by Benveniste, Henson, and Cochrane. The structure of PAF was later elucidated by Demopoulos, Pinckard, and Hanahan in 1979. These studies introduced the research world to PAF, which is now recognised as a potent phospholipid mediator. Since its introduction to the literature, research on PAF has grown due to interest in its vital cell signalling functions and more sinisterly its role as a pro-inflammatory molecule in several chronic diseases including cardiovascular disease and cancer. As it is forty years since the structural elucidation of PAF, the aim of this review is to provide a historical account of the discovery of PAF and to provide a general overview of current and future perspectives on PAF research in physiology and pathophysiology.

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“…In addition, while traditionally considered a proinflammatory cytokine, recent evidence demonstrated that TNF-α promotes mucosal wound repair in mice by activating Wnt/β-catenin signaling, increasing epithelial cell proliferation, and upregulating expression of receptors that promote intestinal healing ( Figure 1 and refs. 32,33).…”

Section: Epithelial Cells In Cutaneous and Intestinal Wound Repairmentioning

confidence: 99%

Innate immune cell–epithelial crosstalk during wound repair

Brazil¹,

Quirós²,

Nusrat³

et al. 2019

Journal of Clinical Investigation

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174

124

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2 9 8 4 jci.org Volume 129 Number 8 August 2019 degrade ECM components. Humans express 24 MMPs that regulate diverse activities important for ECM remodeling and forward movement of the epithelium (reviewed in ref. 19). MMP endoproteinase activity facilitates removal of disorganized structural proteins from healing wounds to make room for newly synthesized collagen. Furthermore, MMP-mediated conversion of type III collagen to more stable type I collagen increases wound tensile strength. Fibroblast-and keratinocyte-derived MMP-1 promotes breakdown of excess collagen in murine and rabbit models of skin repair (20-22). Though not expressed in skin, epithelial cellderived matrilysin (MMP-7) is reportedly the key MMP involved in repairing injured intestinal mucosa in humans (23, 24). Signals that trigger epithelial migration and proliferation from injured sites are incompletely understood. Loss or modification in cell-cell contact and release of intracellular molecules initiates repair (25). These events set the stage for recruiting leukocytes and mesenchymal cells that orchestrate wound repair. Formylated peptides and ATP released by damaged cells, also referred to as damage-associated molecular patterns (DAMPs), orchestrate repair by promoting epithelial cell migration and proliferation. Epithelial wounds are also a source of intracellular Ca ++ waves that are rapidly transmitted into surrounding tissues to influence repair. Furthermore, ROS signaling and wound-associated physical cues influence epithelial repair. Small GTPases in the Rho family regulate remodeling of F-actin, intercellular junctions, and cell-matrix adhesions (26) and are crucial for epithelial cell migration and wound sealing. Similarly, the Rho GTPase Rac1 promotes intestinal epithelial proliferation by targeting β 1-integrin in cellular protrusions and modulating actin dynamics (26). Reparative signaling events are also regulated by extracellular mediators in the epithelial milieu, including annexin A1, annexin A2, and serum amyloid A1, which have been shown to influence integrin localization, focal adhesion kinase activation, and cell matrix remodeling in mouse and human intestinal mucosa (27-30). After injury, chemokines/cytokines and growth factors play crucial roles in epithelial c ell adhesion, migration, proliferation, and differentiation. TGF-β-dependent signaling pathways mediate the regulatory effects of many repair mediators, including PDGF, EGF, VEGF, IL-1, IL-2, IL-6, and IFN-γ (6). Canonical and noncanonical Wnt proteins also modulate epithelial wound repair. A recent in vivo study revealed a role of Wnt5a in orchestrating colonic crypt

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TNFα promotes mucosal wound repair through enhanced platelet activating factor receptor signaling in the epithelium

Cited by 40 publications

References 48 publications

Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing

Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing

Forty Years Since the Structural Elucidation of Platelet-Activating Factor (PAF): Historical, Current, and Future Research Perspectives

Innate immune cell–epithelial crosstalk during wound repair

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