CD9 Is Critical for Cutaneous Wound Healing through JNK Signaling

Abstract

Cutaneous injury triggers a cascade of signaling events essential for wound re-epithelialization. CD9, a cell-surface protein, has been implicated in a number of cellular processes by coupling to intracellular signaling; however, its exact role in wound healing remains unidentified. We reported that CD9 was downregulated in migrating epidermis, and reelevated to basal level when re-epithelialization was completed. Although low level of CD9 appears to be required for normal wound healing, a significant healing delay was found in CD9-null mice, with wounds gaping wider on day 5 and day 7 post wounding. Further analysis showed that re-epithelialization was adversely affected in CD9-null mice, due to impaired migration of epidermis. Notably, CD9 deficiency caused a persistent enhancement of C-JUN NH2 terminal kinase (JNK) signaling primarily in migrating epidermis with abnormal elevation of matrix metalloproteinase (MMP)-9 detected in CD9-null wounds, leading to excessive degradation of type IV collagen, and thus a defective basement membrane at the wound site. JNK suppression reduced MMP-9 production and therefore ameliorated the healing delay with the appearance of significantly elongated migrating epidermis in CD9-null mice. Our study demonstrated the importance of CD9 in wound re-epithelialization, linking this molecule directly to basement membrane formation and epidermal migration through participating in the regulation of the JNK/MMP-9 pathway.

Tetraspanins in Cell Migration

“…The finding that CD9 is downregulated in migrating keratinocytes during wound healing both in vitro and in vivo supports the antimigratory effect of CD9 on keratinocytes under these conditions. 19,20 Similar to CD151-null mice, CD9-null mice show delayed wound healing that is attributed to impaired epidermal migration. Because abnormal elevations of MMP-9 are detected in CD9-null wounds, this delayed epidermal migration may be attributed to excessive degradation of type IV collagen in the basement membrane at the wound site rather than to changes in the migrating keratinocytes themselves.…”

“…[16][17][18] Interestingly, several recent studies have indicated that tetraspanin CD9 regulates the protein expression of MMP-9 via the JNK pathway. 19,20 Tetraspanins also play a role in E-cadherin-based cell-cell junctions. [21][22][23] Although the underlying mechanisms are not fully understood, direct interaction between the tetraspanin CO-029 (TSPAN8) and E-cadherin has been documented by chemical cross-linking and immunohistologic analysis in human colon carcinoma cells.…”

“…Because abnormal elevations of MMP-9 are detected in CD9-null wounds, this delayed epidermal migration may be attributed to excessive degradation of type IV collagen in the basement membrane at the wound site rather than to changes in the migrating keratinocytes themselves. 19 Moreover, because CD9 promotes endothelial cell migration and angiogenesis, 105,106 loss of CD9 might negatively affect angiogenesis at the wound site, additionally contributing to impaired epidermal migration and re-epithelialization. In summary, these data implicate tetraspanins CD151 and CD9 as important regulators of the wound healing process, indicating their role as potential therapeutic targets for pathological wound repair.…”

Les tétraspanines dans la physiopathologie de la peau

“…Seules quelques études récentes ont entrepris l'analyse des voies de signalisation impliquées dans la régulation, au cours de la cicatrisation, de la migration des kératino-cytes par la tétraspanine CD9. Ainsi, pour permettre une cicatrisation correcte, l'expression de CD9 nécessite une régulation fine reposant sur le contrôle de l'activation de la voie de signalisation JNK (c-Jun N-terminal kinase) [17,20,21]. Par des approches de modulation de l'expression de la tétraspanine CD9, il a en effet été montré que la diminution d'expression de CD9 résultait en une baisse d'expression, à la membrane des kérati-nocytes, des intégrines αvβ5 au profit des intégrines αvβ6, entraînant une augmentation de la phosphorylation de JNK qui active la métalloprotéinase-9 (MMP-9) et permet la migration des kératinocytes au point de blessure [17,20,21] (Figure 2).…”

“…Les protéines CD81 et CD151 favorisent la migration cellulaire sur différents types de ligands matriciels [13,15] (Figure 2). L'utilisation de modèles animaux, notamment les souris déficientes pour les gènes CD151 et CD9, a permis de confirmer le rôle de ces tétraspanines in vivo [16,17]. Les kératinocytes isolés de souris CD151 -/-présentent en effet des défauts de migration in vitro et les tests de cicatrisation réalisés in vivo, mettent en évidence un retard de fermeture de la plaie chez les souris CD9 -/-.…”