Interleukin-1 and Transforming Growth Factor Beta: Commonly Opposing, but Sometimes Supporting, Master Regulators of the Corneal Wound Healing Response to Injury
Abstract:Purpose
Interleukin (IL)-1α/IL-1β and transforming growth factor (TGF)β1/TGFβ2 have both been promoted as “master regulators” of the corneal wound healing response due to the large number of processes each regulates after injury or infection. The purpose of this review is to highlight the interactions between these systems in regulating corneal wound healing.
Methods
We conducted a systematic review of the literature.
Results
Both regulator p… Show more
“…In mouse calvarial osteoblasts, TGFβ abolishes the induction of cyclooxygenase 2 by IL1β ( 67 ). TGFβ and IL1β also antagonistically modulate apoptosis of corneal myoblasts ( 68 ). In trophoblasts, TGFβ and IL1β have inhibitory and stimulatory effects, respectively, on cell invasion ( 32 , 69 , 70 ).…”
The acquisition of an endovascular trophoblast (enEVT) phenotype is essential for normal placental development and healthy pregnancy. MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating gene expression. We have recently reported that miR-218-5p promotes enEVT differentiation and spiral artery remodeling in part by targeting transforming growth factor β2 (TGFβ2). We also identified IL1B, which encodes interleukin 1β (IL1β), as one of the most highly upregulated genes by miR-218-5p. In this study, we investigated how miR-218-5p regulates IL1B expression and IL1β secretion and the potential role of IL1β in enEVT differentiation. Using two cell lines derived from extravillous trophoblasts (EVTs), HTR-8/SVneo and Swan 71, we found that stable overexpression of miR-218-5p precursor, mir-218-1, or transient transfection of miR-218-5p mimic, significantly increased IL1B mRNA and IL1β protein levels in cells and conditioned media. We also showed that miR-218-5p directly interacted with SMAD2 3’UTR and reduced SMAD2 at mRNA and protein levels. Knockdown of SMAD2 induced IL1B expression and attenuated the inhibitory effect of TGFβ2 on IL1B expression. On the other hand, overexpression of SMAD2 reduced IL1β levels and blocked the stimulatory effects of miR-218-5p on IL1B expression, trophoblast migration and endothelial-like network formation. In addition, treatment of trophoblasts with IL1β induced the formation of endothelial-like networks and the expression of enEVT markers in a dose-dependent manner. These results suggest that miR-218-5p inhibits the TGFβ/SMAD2 pathway to induce IL1β and enEVT differentiation. Finally, low doses of IL1β also inhibited the expression of miR-218-5p, suggesting the existence of a negative feedback regulatory loop. Taken together, our findings suggest a novel interactive miR-218-5p/TGFβ/SMAD2/IL1β signaling nexus that regulates enEVT differentiation.
“…In mouse calvarial osteoblasts, TGFβ abolishes the induction of cyclooxygenase 2 by IL1β ( 67 ). TGFβ and IL1β also antagonistically modulate apoptosis of corneal myoblasts ( 68 ). In trophoblasts, TGFβ and IL1β have inhibitory and stimulatory effects, respectively, on cell invasion ( 32 , 69 , 70 ).…”
The acquisition of an endovascular trophoblast (enEVT) phenotype is essential for normal placental development and healthy pregnancy. MicroRNAs (miRNAs) are small noncoding RNAs that play critical roles in regulating gene expression. We have recently reported that miR-218-5p promotes enEVT differentiation and spiral artery remodeling in part by targeting transforming growth factor β2 (TGFβ2). We also identified IL1B, which encodes interleukin 1β (IL1β), as one of the most highly upregulated genes by miR-218-5p. In this study, we investigated how miR-218-5p regulates IL1B expression and IL1β secretion and the potential role of IL1β in enEVT differentiation. Using two cell lines derived from extravillous trophoblasts (EVTs), HTR-8/SVneo and Swan 71, we found that stable overexpression of miR-218-5p precursor, mir-218-1, or transient transfection of miR-218-5p mimic, significantly increased IL1B mRNA and IL1β protein levels in cells and conditioned media. We also showed that miR-218-5p directly interacted with SMAD2 3’UTR and reduced SMAD2 at mRNA and protein levels. Knockdown of SMAD2 induced IL1B expression and attenuated the inhibitory effect of TGFβ2 on IL1B expression. On the other hand, overexpression of SMAD2 reduced IL1β levels and blocked the stimulatory effects of miR-218-5p on IL1B expression, trophoblast migration and endothelial-like network formation. In addition, treatment of trophoblasts with IL1β induced the formation of endothelial-like networks and the expression of enEVT markers in a dose-dependent manner. These results suggest that miR-218-5p inhibits the TGFβ/SMAD2 pathway to induce IL1β and enEVT differentiation. Finally, low doses of IL1β also inhibited the expression of miR-218-5p, suggesting the existence of a negative feedback regulatory loop. Taken together, our findings suggest a novel interactive miR-218-5p/TGFβ/SMAD2/IL1β signaling nexus that regulates enEVT differentiation.
“…Emerging evidence has demonstrated that the activation of the NLRP3 inflammasome involves an inflammatory response, which is mainly driven by the release of proinflammatory cytokine IL-1β and IL-18. 29 , 30 Coincidentally, IL-1β plays a pivotal role in the pathogenesis of inflammation and fibrosis 31 , 32 ; moreover, it amplifies the effects of other cytokines. 18 In liver diseases, the NLRP3 inflammasome activation indirectly induces liver inflammation and fibrosis in a cytokine-dependent manner.…”
Purpose
To explore the effect and mechanism of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasomes on corneal fibrosis.
Methods
The wild-type,
NLRP3
knockout (KO), and myeloid cell-specific
NLRP3
KO (
NLRP3
Lyz-KO) C57 mice were used to establish a corneal scarring model. NLRP3 inhibitor, IL-1β neutralizing antibody, and an IL-1R antagonist were used to investigate the role of NLRP3 and IL-1β in corneal fibrosis. The expression of the NLRP3 signaling pathway related proteins, alpha-smooth muscle actin, TGF-β was determined by quantitative real-time polymerase chain reaction, Western blotting, and immunofluorescence staining. Flow cytometry was used to detect the infiltration of macrophages during corneal fibrosis.
Results
The components of the NLRP3 inflammasomes were elevated and activated during corneal scarring. Additionally, genetic or chemical-mediated blocking of NLRP3 as well as IL-1β significantly alleviated corneal fibrosis. Moreover, neutrophil (CD45
+
Ly6G
+
) and macrophage (CD45
+
F4/80
+
) accumulation increased in the cornea during the progression of corneal fibrosis. Intriguingly, the increased concentrations of NLRP3 and IL-1β were prominently colocalized with the infiltrating F4/80
+
macrophages. Expectedly, NLRP3 Lyz-KO mice exhibited a marked decrease in their corneal fibrosis symptoms. Mechanistically, the activation of IL-1β or macrophage NLRP3 stimulated the expression of TGF-β1 in the corneal epithelial cells, whereas an NLRP3 deficiency decreased its expression in the corneal epithelium.
Conclusions
These observations revealed that the NLRP3 inflammasome activation in infiltrating macrophages contributes to corneal fibrosis by regulating corneal epithelial TGF-β1 expression. Targeting the NLRP3 inflammasome might be a promising strategy for the treatment of corneal scarring.
“…IL-1 alpha released by epithelial or endothelial injury triggers other important functions in corneal fibroblasts. 66 Gene array experiments 67 demonstrated that IL-1 alpha (and tumor necrosis factor-alpha) stimulate the transcription of many chemokines, such as monocyte-derived neutrophil chemotactic factor, chemokine (C–C motif) ligand 2, also called monocyte chemoattractant protein-1, granulocyte colony-stimulating factor, and C-X-C motif chemokine 5 (also called neutrophil-activating peptide or ENA-78), that amplify the effect of IL-1 alpha itself in drawing not only fibrocytes, but other bone marrow-derived cells, such as lymphocytes, neutrophils, and macrophages, into the corneal stroma. IL-1 alpha also upregulates the production of hepatocyte growth factor and keratinocyte growth factor (or fibroblast growth factor-7) 68 , 69 that stimulate epithelial healing by modulating the proliferation, motility, differentiation, and apoptosis of corneal epithelial cells.…”
Section: Contributions Of Corneal Nerves To Transparencymentioning
Purpose
To highlight the cellular, matrix, and hydration changes associated with opacity that occurs in the corneal stroma after injury.
Methods
Review of the literature.
Results
The regulated transition of keratocytes to corneal fibroblasts and myofibroblasts, and of bone marrow-derived fibrocytes to myofibroblasts, is in large part modulated by transforming growth factor beta (TGFβ) entry into the stroma after injury to the epithelial basement membrane (EBM) and/or Descemet's membrane. The composition, stoichiometry, and organization of the stromal extracellular matrix components and water is altered by corneal fibroblast and myofibroblast production of large amounts of collagen type I and other extracellular matrix components—resulting in varying levels of stromal opacity, depending on the intensity of the healing response. Regeneration of EBM and/or Descemet's membrane, and stromal cell production of non-EBM collagen type IV, reestablishes control of TGFβ entry and activity, and triggers TGFβ-dependent myofibroblast apoptosis. Eventually, corneal fibroblasts also disappear, and repopulating keratocytes reorganize the disordered extracellular matrix to reestablish transparency.
Conclusions
Injuries to the cornea produce varying amounts of corneal opacity depending on the magnitude of cellular and molecular responses to injury. The EBM and Descemet's membrane are key regulators of stromal cellularity through their modulation of TGFβ. After injury to the cornea, depending on the severity of the insult, and possibly genetic factors, trace opacity to severe scarring fibrosis develops. Stromal cellularity, and the functions of different cell types, are the major determinants of the level of the stromal opacity.
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