PARP‐1 involves in UVB‐induced inflammatory response in keratinocytes and skin injury via regulation of ROS‐dependent EGFR transactivation and p38 signaling

Abstract

UV irradiation can injure the epidermis, resulting in sunburn, inflammation, and cutaneous tissue disorders. Previous studies demonstrate that EGFR in keratinocytes can be activated by UVB and contributes to inflammation. Poly (ADP‐ribose) polymerase‐1 (PARP‐1) is a nuclear enzyme and plays an essential role in DNA repair under moderate stress. In this study, we set out to understand how PARP‐1 regulates UVB irradiation‐induced skin injury and interplays with EGFR to mediate the inflammation response. We found that PARP‐1 deficiency exacerbated the UVB‐induced inflammation, water loss, and back skin damage in mice. In human primary keratinocytes, UVB can activate PARP‐1 and enhance DNA damage upon PARP‐1 gene silencing. Moreover, PARP‐1 silencing and PARP inhibitor olaparib can suppress UVB‐induced COX‐2 and MMP‐1 expression, but enhance TNF‐α and IL‐8 expression. In addition, EGFR silencing or EGFR inhibition by gefitinib can decrease UVB‐induced COX‐2, TNF‐α, and IL‐8 expression, suggesting EGFR activation via paracrine action can mediate UVB‐induced inflammation responses. Immunoblotting data revealed that PARP‐1 inhibition decreases UVB‐induced EGFR and p38 activation. Pharmacological inhibition of p38 also dramatically led to the attenuation of UVB‐induced inflammatory gene expression. Of note, genetic ablation of PARP‐1 or EGFR can attenuate UVB‐induced ROS production, and antioxidant NAC can attenuate UVB‐induced EGFR‐p38 signaling axis and PARP‐1 activation. These data suggest the regulatory loops among EGFR, PARP‐1, and ROS upon UVB stress. PARP‐1 not only serves DNA repair function but also orchestrates interactions to EGFR transactivation and ROS production, leading to p38 signaling for inflammatory gene expression in keratinocytes.

Protective Effect of Potentilla glabra in UVB-Induced Photoaging Process

“…Cui et al found that the ratio of Bcl-2 and Bax decreased, while p-ERK1/2 was up-regulated by UVB [ 64 ]. Chiu et al demonstrated that the p38 signaling pathway was also involved in UVB-induced photoaging in keratinocytes [ 65 ]. Ko et al also found that Nrf2 was suppressed by UVB and alleviated by ergothioneine [ 66 ].…”

PARP-1 regulates inflammasome activity by poly-ADP-ribosylation of NLRP3 and interaction with TXNIP in primary macrophages

“…ROS can be generated by all known NLRP3 activators to activate inflammasome [ 18 , 19 ]. Upon oxidative stress-induced DNA damage, PARP-1 can be activated by ROS and reciprocally further increase ROS production [ 33 ]. As we observed the decreased inflammasome complex formation in Parp-1 −/− BMDM, we wondered whether PARP-1 also plays a role in NLRP3 activators-induced ROS production.…”

“…5 d). Intriguingly, our previous work also showed that PARP-1 can positively regulate UVB-induced ROS production in keratinocytes which is partially resulting from EGFR transactivation [ 33 ]. Another study mentioned that PARP-1 activation by oxidative stress contributes to the impairment of mitochondrial integrity by decreasing MKP-1 expression in an ATF4-dependent manner then activating p38 and JNK, leading to mitochondrial ROS production [ 50 ].…”

Blimp-1 Upregulation by Multiple Ligands via EGFR Transactivation Inhibits Cell Migration in Keratinocytes and Squamous Cell Carcinoma

“…Human immortalized HaCaT keratinocytes, oral SCC Cal-27 and SAS cells were cultured in high glucose Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% FBS and 1% penicillin-streptomycin-amphotericin B. NHEKs (normal human epidermal keratinocytes) were obtained from normal adult human foreskin and isolated as described previously (Chiu et al, 2021). The experiments were conducted according to the Declaration of Helsinki principles and approved by the Ethics Committee of Mackay Memorial Hospital (Institutional Review Board codes 19MMHIS173e).…”

“…TLRs, the major pattern recognition receptors for host defense, are expressed in keratinocytes (Lebre et al, 2007). On the other hands, UVB and reactive oxygen species (ROS) can lead to DNA damageassociated EGFR transactivation and inflammation in keratinocyte (Chiu et al, 2021). Moreover, the role of Blimp-1 in cell migration of keratinocytes and SCC was addressed.…”