IL-4 impairs wound healing potential in the skin by repressing fibronectin expression

Serezani, Ana Paula Moreira; Bozdoğan, Günseli; Sehra, Sarita; Walsh, Daniel J.; Krishnamurthy, Purna; Potchanant, Elizabeth Sierra; Nalepa, Grzegorz; Goenka, Shreevrat; Turner, Matthew J.; Spandau, Dan F.; Kaplan, Mark H.

doi:10.1016/j.jaci.2016.07.012

Cited by 59 publications

(42 citation statements)

References 50 publications

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“…Consistent with this notion, it has been recently demonstrated that excisional wound closure is significantly delayed in mice overexpressing IL-4 or the active form of STAT6, a transcription factor critical for the IL-4/IL-13 signals that manifest ADlike skin disorders. 40,41 These results support the intriguing possibility that periostin mis-expression may be involved in the impaired wound repair seen in AD patients.…”

Section: Discussionsupporting

confidence: 63%

Constitutive overexpression of periostin delays wound healing in mouse skin

Nunomura

Nanri

Ogawa

et al. 2018

Wound Repair Regeneration

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Periostin is a matricellular protein involved in development, maintenance, and regulation of tissues and organs via by binding to cell surface integrin receptors. Pathologically, periostin plays an important role in the process of wound healing: as a deficiency of the Postn gene delays wound closure and periostin is consistently up-regulated in response to injury and skin diseases. However, the functional role of elevated periostin in the process of wound healing has not been tested. In this study, we generated Postn-transgenic mice under the control of the CAG promoter/enhancer to investigate the effects of constitutive overexpression of full length periostin during its pathophysiological roles. Transgenic mice showed significant overexpression of periostin in skin, lung, and heart, but no morphological changes were observed. However, when these transgenic mice were injured, periostin overexpression delayed the closure of excisional wounds. Expression of IL-1β and TNFα, pro-inflammatory cytokines important for wound healing, was significantly decreased in the transgenic mice, prior to delayed healing. Infiltration of neutrophils and macrophages, the main sources of IL-1β and TNFα, was also down-regulated in the transgenic wound sites. From these data, we conclude that enforced expression of periostin delays wound closure due to reduced infiltration of neutrophils and macrophages followed by down-regulation of IL-1β and TNFα expression. This suggests that regulated spatiotemporal expression of periostin is important for efficient wound healing and that constitutive periostin overexpression interrupts the normal process of wound closure.

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Section: Discussionsupporting

confidence: 63%

Constitutive overexpression of periostin delays wound healing in mouse skin

Nunomura

Nanri

Ogawa

et al. 2018

Wound Repair Regeneration

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show abstract

“…In the airways, IL-13 has been shown to induce mucus production via the IL-4-receptor α, Stat6 and Spdef pathway [47,48]. This pathway has been implicated in healing, but with contrasting results: IL-4 has been demonstrated to impair wound healing in the skin [50], whereas Stat6 −/mice display delayed wound healing in mice treated with 2,4,6-trinitrobenzenesulfonic acid [51] We have previously shown that mucin production and vesicle transport rate decrease during acute and chronic infection with Helicobacter pylori in the murine stomach [52]. Similar to C. rodentium, H. pylori is associated with a Th1/17 cytokine response, but in contrast, H. pylori causes a chronic infection associated with reduced expression of IL-4 [53].…”

Section: Discussionmentioning

confidence: 99%

Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis andCitrobacter rodentiumin contact with epithelial cells

et al. 2019

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Citrobacter rodentium infection is a murine model for pathogenic intestinal Escherichia coli infection. C. rodentium infection causes an initial decrease in mucus layer thickness, followed by an increase during clearance. We aimed to identify the cause of these changes and to utilize this naturally occurring mucus stimulus to decrease pathogen impact and inflammation. We identified that mucin production and speed of transport from Golgi to secretory vesicles at the apical surface increased concomitantly with increased mucus thickness. Of the cytokines differentially expressed during increased mucus thickness, IFN-γ and TNF-α decreased the mucin production and transport speed, whereas IL-4, IL-13, C. rodentium and E. coli enhanced these aspects. IFN-γ and TNF-α treatment in combination with C. rodentium and pathogenic E. coli infection negatively affected mucus parameters in vitro, which was relieved by IL-4 treatment. The effect of IL-4 was more pronounced than that of IL-13, and in wild type mice, only IL-4 was present. Increased expression of Il-4, Il-4-receptor α, Stat6 and Spdef during clearance indicate that this pathway contributes to the increase in mucin production. In vivo IL-4 administration initiated 10 days after infection increased mucus thickness and quality and decreased colitis and pathogen contact with the epithelium. Thus, during clearance of infection, the concomitant increase in IL-4 protects and maintains goblet cell function against the increasing levels of TNF-α and IFN-γ. Furthermore, IL-4 affects intestinal mucus production, pathogen contact with the epithelium and colitis. IL-4 treatment may thus have therapeutic benefits for mucosal healing.

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“…Furthermore, Treg depletion caused severe autoimmune gastritis that was ameliorated by loss of IL‐4 . Interestingly, negative effects of increased levels of IL‐4 on wound healing have been described , suggesting that upregulation of this cytokine further contributes to the impaired healing in Treg‐depleted mice. However, preliminary experiments showed that antibody‐mediated IL‐4 neutralization does not rescue the wound healing defect in Treg‐depleted mice, but rather has the opposite effect.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T cells are required for normal and activin‐promoted wound repair in mice

et al. 2018

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Healing of skin wounds is orchestrated by various types of immune cells, but little is known about the role of FoxP3 regulatory T cells (Tregs) in this process. Here, we determined if Tregs are important for wound healing in normal mice and if they contribute to the accelerated healing of mice overexpressing the growth and differentiation factor activin. Diphtheria toxin induced Treg depletion prior to injury caused impaired healing characterized by delayed reepithelialization, reduced wound contraction, and impaired vessel maturation. The accelerated wound repair of activin-transgenic mice was also abrogated. Mechanistically, we found a strong increase in IL-4 levels combined with overrepresentation of T-bet and GATA-3 αβ T cells in Treg-depleted 7-day wounds. In addition, numbers of IFN-γ- or IL-17A-producing CD4 and CD4 T cells were elevated. These results demonstrate that Treg depletion in wounds facilitates the expansion of an αβ T-cell population with features of Th1 and Th2 cells, and suggest that concomitant changes in the cytokine milieu disturb the healing process.

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IL-4 impairs wound healing potential in the skin by repressing fibronectin expression

Cited by 59 publications

References 50 publications

Constitutive overexpression of periostin delays wound healing in mouse skin

Constitutive overexpression of periostin delays wound healing in mouse skin

Interleukin 4 induces rapid mucin transport, increases mucus thickness and quality and decreases colitis andCitrobacter rodentiumin contact with epithelial cells

Regulatory T cells are required for normal and activin‐promoted wound repair in mice

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