Poly(ADP‐ribose) polymerase‐1 depletion enhances the severity of inflammation in an imiquimod‐induced model of psoriasis

Abstract

Poly(ADP‐ribose) polymerase‐1 (PARP1) is a pro‐inflammatory protein, whose pro‐inflammatory properties were demonstrated in human. The pro‐inflammatory properties of PARP1 were shown in Th1‐ and Th2‐mediated inflammatory pathologies, but not Th17‐mediated inflammation. Thus, we studied the role of PARP1 in the imiquimod‐induced model of psoriasis. To our surprise, in imiquimod‐induced psoriasis, PARP1 acted as an anti‐inflammatory factor and its genetic deletion exacerbated symptoms. We showed that in the absence of PARP1, the epidermis thickened and the number of TUNEL‐positive cells decreased in the epidermis. These data indicate programmed cell death is decreased in keratinocytes. Changes in involucrin expression suggest that keratinocyte differentiation is hampered. Furthermore, epidermal expression of IL6 increased in the psoriasiform lesions of PARP1 knockout mice, suggesting that the inflammatory response is also derailed in the absence of PARP1. Finally, we showed that PARP1 expression is reduced in human psoriatic lesions compared with control skin samples. In imiquimod‐treated HPV‐KER keratinocytes, PARP inhibition recapitulated the in vivo findings, namely keratinocyte hyperproliferation; furthermore, the mRNA expression of psoriasis‐associated cytokines (IL6, IL1β, IL8, IL17 and IL23A) was also induced. The inhibition of TRPV1 abrogated the effects of the combined imiquimod + PARP inhibitor treatment.

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

“…Similar to our findings is a recent study showing PARP‐1 depletion enhances the severity of inflammation in an imiquimod‐induced model of psoriasis 59 . Moreover, data from using HPV‐KER keratinocytes recapitulate the in vivo findings of PARP‐1, that is, PARP‐1 inhibition can upregulate the gene expression of psoriasis‐associated cytokines like IL‐6, IL‐1β, IL‐8, IL‐17, and IL‐23A 59 . Therefore, we speculate the increased inflammatory mediators such as TNF‐α and chemokines (eg, IL‐8) in PARP‐1‐deficient keratinocytes might contribute to the increased severity of mouse skin injury after UVB irradiation.…”

“…In this study, we observe more severe skin injury in Parp‐1 −/− mice upon UVB insult. Similar to our findings is a recent study showing PARP‐1 depletion enhances the severity of inflammation in an imiquimod‐induced model of psoriasis 59 . Moreover, data from using HPV‐KER keratinocytes recapitulate the in vivo findings of PARP‐1, that is, PARP‐1 inhibition can upregulate the gene expression of psoriasis‐associated cytokines like IL‐6, IL‐1β, IL‐8, IL‐17, and IL‐23A 59 .…”

Multifaceted Role of PARP-1 in DNA Repair and Inflammation: Pathological and Therapeutic Implications in Cancer and Non-Cancer Diseases

“…No significant differences in IL-17 production were also observed in an imiquimod-induced model of psoriasis, a finding deserving further studies to clarify the role of PARP-1 in Th17-cell driven inflammation. Curiously, PARP-1 depletion enhanced the severity of psoriasis-associated inflammation [128]. Moreover, ex vivo stimulation of purified naïve CD4 cells from PARP-1KO mice generates Th17 cells with a frequency similar to wild type cells [104].…”

The role of ADP-ribose metabolism in metabolic regulation, adipose tissue differentiation, and metabolism

“…Furthermore, inflammatory signaling seems to be a player in diverting toward the beige lineage (Sun et al 2018). PARP enzymes are involved in the regulation of inflammation; usually, the absence of PARP1 or PARP2 or pharmacological PARP inhibition is anti-inflammatory (Fehr et al 2020), except for Th17-mediated processes (Kiss et al 2019). Furthermore, increases in SIRT1 activity, which can be elicited by PARP inhibition, can suppress adipose tissue inflammation, and hence support its function (Gillum et al 2011;Chalkiadaki and Guarente 2012).…”