Niacinamide mitigates SASP‐related inflammation induced by environmental stressors in human epidermal keratinocytes and skin

Abstract

Objective To evaluate whether niacinamide (Nam) can mitigate production of inflammatory and senescence‐related biomarkers induced by environmental stressors. Methods Human epidermal keratinocytes were exposed to UVB, urban dust, diesel exhaust and cigarette smoke extract and treated with Nam or vehicle control. Full thickness 3‐D skin organotypic models were exposed to a combination of UVB and PM2.5 and treated with Nam or vehicle control. Quantitation of the SASP‐related inflammatory mediators PGE2, IL‐6 and IL‐8 was performed on cultured media. UVB‐exposed keratinocytes treated with and without Nam were immunostained for the senescence biomarker Lamin B1 (LmnB1). Transcriptomics profiling of cigarette smoke extract effects on keratinocytes was performed. A double‐blind, placebo‐controlled clinical was conducted on 40 female panellists that were pretreated on back sites for two weeks with 5% Nam or vehicle and then exposed to 1.5 minimal erythemal dose (MED) solar‐simulated radiation (SSR). Treated sites were compared with non‐treated exposed sites for erythema and the skin surface IL‐1αRA/IL‐1α inflammatory biomarkers. Results Ultraviolet B induced synthesis of PGE2, IL‐8 and IL‐6 and reduced LmnB1 levels in keratinocytes. Urban dust and diesel exhaust only stimulated synthesis of IL‐8 whereas cigarette smoke extract only stimulated levels of PGE2. In all exposures, treatment with Nam significantly mitigated synthesis of the inflammatory mediators and restored levels of UVB‐reduced LmnB1. In the 3D skin equivalent model, Nam reduced IL‐8 levels stimulated by a combination of topical PM2.5 and UV exposure. In a UV challenge clinical, pretreatment with 5% Nam reduced erythema and skin surface IL‐1αRA/IL‐1α inflammatory biomarkers that were induced by SSR. Conclusion Since it is known that Nam has anti‐inflammatory properties, we tested whether Nam can inhibit environmental stress‐induced inflammation and senescence‐associated secretory phenotype (SASP) biomarkers. We show Nam can reduce PGE2, IL‐6 and IL‐8 levels induced by environmental stressors. Additionally, in vivo pretreatment with Nam can reduce UV‐induced erythema and skin surface inflammatory biomarkers. These findings add to the body of evidence that Nam can mitigate the skin’s inflammatory response elicited by environmental stressors. This supports Nam can potentially inhibit senescence and premature ageing and thereby maintain skin’s functionality and appearance.

Mechanistic Basis and Clinical Evidence for the Applications of Nicotinamide (Niacinamide) to Control Skin Aging and Pigmentation

“…The supply of nicotinamide helps to normalize these changes, delaying cell senescence and extending its lifespan [ 72 , 74 , 75 , 77 ]. Nicotinamide inhibits the production of inflammatory cytokines and PGs in keratinocytes or in three-dimensional skin models that are exposed to UV radiation [ 58 , 59 ]. Nicotinamide decreases ECM-degrading enzymes and increases collagen synthesis in dermal fibroblasts [ 100 , 101 , 102 ].…”

“…Nicotinamide attenuated the synthesis of inflammatory mediators, such as prostaglandin (PG) E 2 , IL-6, and IL-8 in human epidermal keratinocytes and in full-thickness three-dimensional skin organotypic models that were stimulated by UV radiation [ 59 ]. In a clinical trial, pretreatment with 5% nicotinamide reduced erythema that was induced by UV radiation [ 59 ].…”

“…Nicotinamide attenuated the synthesis of inflammatory mediators, such as prostaglandin (PG) E 2 , IL-6, and IL-8 in human epidermal keratinocytes and in full-thickness three-dimensional skin organotypic models that were stimulated by UV radiation [ 59 ]. In a clinical trial, pretreatment with 5% nicotinamide reduced erythema that was induced by UV radiation [ 59 ]. Analysis of IL-1α and its receptor antagonist (IL-1αRA) ratios showed that nicotinamide significantly reduced the UV-induced inflammatory response, compared to the control sites.…”

Purified Cannabidiol isolate does not inhibit active caspase‐1 release in NLRP inflammasome‐mediated UVB or ATP‐activated keratinocytes or appear to reduce key inflammatory cytokines in UVB‐irradiate keratinocytes

“…After failing to demonstrate anti‐inflammatory effects in the NLRP‐mediated pathways studies, the same CBD Isolate was examined for its anti‐inflammatory effects in non‐NLRP inflammasome‐mediated pathways after UVB irradiation. Again, the CBD Isolate failed to demonstrate anti‐inflammatory behaviour in these models that examined UVB‐mediated release of IL‐6, IL‐8 and PGE 2 , well‐known markers for epidermal inflammatory response to UVB [17].…”

Skin Aging, Cellular Senescence and Natural Polyphenols

“…Moreover, UVB-induced DNA damage in the keratinocytes was reported to initiate MMP-1 release by fibroblasts [ 197 ]. On the other hand, UVB radiation induced the synthesis of SASP-related inflammatory mediators prostaglandin E2 (PGE2), IL-8 and IL-6, and reduced lamin B1 levels in human epidermal keratinocytes [ 198 ]. UV irradiation also causes gene mutations in key elements of the TGFβ signaling pathway, including TGFβRI , TGFβRII , SMAD2 and SMAD4 , resulting in the promotion of cancer development [ 199 ], as well as photoaging and chronological aging through a reduction in type I procollagen synthesis [ 200 ].…”