Diabetic Wound Keratinocytes Induce Macrophage JMJD3-Mediated Nlrp3 Expression via IL-1R Signaling.
Diabetes
; 73(9): 1462-1472, 2024 Sep 01.
Article
in En
| MEDLINE
| ID: mdl-38869447
ABSTRACT
Macrophage (Mφ) plasticity is critical for normal wound repair; however, in type 2 diabetic wounds, Mφs persist in a low-grade inflammatory state that prevents the resolution of wound inflammation. Increased NLRP3 inflammasome activity has been shown in diabetic wound Mφs; however, the molecular mechanisms regulating NLRP3 expression and activity are unclear. Here, we identified that diabetic wound keratinocytes induce Nlrp3 gene expression in wound Mφs through IL-1 receptor-mediated signaling, resulting in enhanced inflammasome activation in the presence of pathogen-associated molecular patterns and damage-associated molecular patterns. We found that IL-1α is increased in human and murine wound diabetic keratinocytes compared with nondiabetic controls and directly induces Mφ Nlrp3 expression through IL-1 receptor signaling. Mechanistically, we report that the histone demethylase, JMJD3, is increased in wound Mφs late post-injury and is induced by IL-1α from diabetic wound keratinocytes, resulting in Nlrp3 transcriptional activation through an H3K27me3-mediated mechanism. Using genetically engineered mice deficient in JMJD3 in myeloid cells (Jmjd3f/flyz2Cre+), we demonstrate that JMJD3 controls Mφ-mediated Nlrp3 expression during diabetic wound healing. Thus, our data suggest a role for keratinocyte-mediated IL-1α/IL-1R signaling in driving enhanced NLRP3 inflammasome activity in wound Mφs. These data also highlight the importance of cell cross-talk in wound tissues and identify JMJD3 and the IL-1R signaling cascade as important upstream therapeutic targets for Mφ NLRP3 inflammasome hyperactivity in nonhealing diabetic wounds.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Wound Healing
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Signal Transduction
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Keratinocytes
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Receptors, Interleukin-1
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Jumonji Domain-Containing Histone Demethylases
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Inflammasomes
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NLR Family, Pyrin Domain-Containing 3 Protein
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Macrophages
Limits:
Animals
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Humans
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Male
Language:
En
Journal:
Diabetes
Year:
2024
Document type:
Article
Country of publication: