Autocrine IL-1β mediates the promotion of corneal neovascularization by senescent fibroblasts

Dong, Meirong; Yang, Lingling; Qu, Mingli; Hu, Xiaoli; Zhang, Xiaoping; Shi, Weiyun; Zhou, Qingjun

doi:10.1152/ajpcell.00205.2017

Cited by 7 publications

(6 citation statements)

References 51 publications

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“…A gain-of-function variant in NLRP3 leads to keratitis fugax hereditaria [23], with inflammatory attacks affecting the ocular surface. Additionally, persistent activation of the NLRP3 inflammasome has been found in both pterygium and keloids [24][25][26][27][28].…”

Section: Discussionmentioning

confidence: 99%

A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

et al. 2023

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Edited by Wilfried EllmeierOcular pterygium-digital keloid dysplasia (OPDKD) is a rare hereditary disease characterized by corneal ingrowth of vascularized conjunctival tissue early in life. Later, patients develop keloids on fingers and toes but are otherwise healthy. In a recently described family with OPDKD, we report the presence of a de novo c.770C > T, p.(Thr257Ile) variant in PELI2 in the affected individual. PELI2 encodes for the E3 ubiquitin ligase Pellino-2. In transgenic U87MG cells overexpressing Pellino-2 with the p.(Thr257Ile) amino acid substitution, constitutive activation of the NLRP3 inflammasome was observed. However, the Thr257Ile variant did not affect Pellino-2 intracellular localization, its binding to known interaction partners, nor its stability. Our findings indicate that constitutive autoactivation of the NLRP3 inflammasome contributes to the development of PELI2-associated OPDKD.

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Section: Discussionmentioning

confidence: 99%

A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

et al. 2023

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“… 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. 33 In contrast, activation of the inflammasome in hepatic stellate cells directly promotes liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“… 15 – 17 Moreover, recent studies have reported that IL-1β induces apoptosis of corneal stromal cells and participates in the repair of corneal injuries, as well as in corneal neovascularization. 18 , 19 However, the involvement of the NLRP3/IL-1β pathway of macrophages in corneal stromal cell activation and corneal scar formation is yet to be confirmed.…”

mentioning

confidence: 99%

The NLRP3 Activation in Infiltrating Macrophages Contributes to Corneal Fibrosis by Inducing TGF-β1 Expression in the Corneal Epithelium

Chen

Luan

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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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.

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“…However, when clearance of these cells becomes compromised, for example, due to an ageing immune system, they accumulate in tissues [ 2 ]. By their nature, senescent cells secrete a variety of bioactive molecules including chemokines, growth factors and reactive oxygen species (ROS) that engage in autocrine and paracrine interactions to influence the local microenvironment [ 3 , 4 , 5 ]. Senescence can result from excessive mitotic division, also referred to as mitotic ageing, or as a response to severe stress.…”

Section: Introductionmentioning

confidence: 99%

A Senescence Bystander Effect in Human Lung Fibroblasts

et al. 2021

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Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by a dense fibrosing of the lung parenchyma. An association between IPF and cellular senescence is well established and several studies now describe a higher abundance of senescent fibroblasts and epithelial cells in the lungs of IPF patients compared with age-matched controls. The cause of this abnormal accumulation of senescent cells is unknown but evidence suggests that, once established, senescence can be transferred from senescent to non-senescent cells. In this study, we investigated whether senescent human lung fibroblasts (LFs) and alveolar epithelial cells (AECs) could induce a senescent-like phenotype in “naïve” non-senescent LFs in vitro. Primary cultures of LFs from adult control donors (Ctrl-LFs) with a low baseline of senescence were exposed to conditioned medium (CM) from: (i) Ctrl-LFs induced to become senescent using H2O2 or etoposide; (ii) LFs derived from IPF patients (IPF-LFs) with a high baseline of senescence; or (iii) senescence-induced A549 cells, an AEC line. Additionally, ratios of non-senescent Ctrl-LFs and senescence-induced Ctrl-LFs (100:0, 0:100, 50:50, 90:10, 99:1) were co-cultured and their effect on induction of senescence measured. We demonstrated that exposure of naïve non-senescent Ctrl-LFs to CM from senescence-induced Ctrl-LFs and AECs and IPF-LFs increased the markers of senescence including nuclear localisation of phosphorylated-H2A histone family member X (H2AXγ) and expression of p21, IL-6 and IL-8 in Ctrl-LFs. Additionally, co-cultures of non-senescent and senescence-induced Ctrl-LFs induced a senescent-like phenotype in the non-senescent cells. These data suggest that the phenomenon of “senescence-induced senescence” can occur in vitro in primary cultures of human LFs, and provides a possible explanation for the abnormal abundance of senescent cells in the lungs of IPF patients.

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Autocrine IL-1β mediates the promotion of corneal neovascularization by senescent fibroblasts

Cited by 7 publications

References 51 publications

A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

A Pellino‐2 variant is associated with constitutive NLRP3 inflammasome activation in a family with ocular pterygium–digital keloid dysplasia

The NLRP3 Activation in Infiltrating Macrophages Contributes to Corneal Fibrosis by Inducing TGF-β1 Expression in the Corneal Epithelium

A Senescence Bystander Effect in Human Lung Fibroblasts

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