Ultraviolet Induced Skin Inflammation

Hai-Chao Zhao, Ta Xiao, Yu-Jie Chen

Hospital for Skin Diseases (Institute of Dermatology), Chinese Academy of Medical Sciences and Peking Union Medical College,Nanjing, Jiangsu 210042, China.

Abstract Ultraviolet(UV)induced skin inflammation(UISI)is associated with many skin disorders.However,the mechanism by which UV causes skin inflammation remains unclear.Studies evaluating UISI in vivo have mainly been conducted using mouse models.Current investigations indicate that the classic inflammatory pathways involving nuclear factor kappa B and Toll-like receptor contribute to the regulation of UISI.However,more novel signaling factors have been identified as being involved in this process, including interleukin 22 receptor-α, cluster of differentiation 28 and cluster of differentiation 1d, serum amyloid A1, estrogen, melatonin, peroxisome proliferator activated receptors β/δ, isocitrate dehydrogenase 2, and transglutaminase 2.In addition, the gene mutation of fermitin family member 1 and selenium deficiency are reported to affect the phenotype of UISI.Although the actual roles of UISI in UV-related skin diseases need to be clarified, recent studies have reported the potent contribution of UISI to photocarcinogesis.To clarify the process and modulation of UISI,the special profiles of cytokines and inflammatory mediators and the core regulatory pathways should be identified clearly.These investigations would be promoted rapidly, accompanied by the conduction of high-quality clinical research on patients with UV-related skin disease and the construction of precise animal models of UISI.

Keywords: inflammation, skin, ultraviolet

Introduction

Solar ultraviolet (UV) exposure, mainly UVA (315-400 nm)and UVB(280-315 nm),1is one important pathogenic factor causing skin disorders.UV radiation can lead to numerous pathological manifestations of the skin, and inflammation is a crucial process among these UV-induced effects.UV-induced skin inflammation (UISI) is closely associated with the pathogenesis of many UV-associated skin diseases.In fact,adjustable inflammation is a normal self-defense mechanism.However, excessive and unregulated inflammatory reactions contribute to various diseases.UISI is reported to have a close relationship with nonmelanoma skin cancer.2Emerging evidence has demonstrated that the dysregulation of the nuclear factor kappa-B (NF-κB) and toll-like receptor (TLR) pathways contribute to the process of UISI.3-4Furthermore,cytokines like interleukin(IL)-1a,IL-6,and tumor necrosis factor-a (TNF-α) are closely associated with this inflammation process.5-6They showed different levels of increase after UV exposure.7–8However, the exact mechanism of UISI remains unclear, so we summarized the research process from literature using the searching strategy “(UV AND inflammation)OR(ultraviolet AND inflammation)”in Title/Abstarct on PubMed from 2014-2020.

Characteristics and signs of UV-induced inflammation

Inflammation is induced by many kinds of endogenous and exogenous stimulations of the human body.9Dysregulated inflammation contributes to many skin disorders, manifesting as erythema, swelling, heat, pain, or loss of function.9However, not all of these symptoms are found in the single process of inflammation.

When UV radiation reaches the skin, about 5% is reflected, while the other 95% is transmitted, scattered,and absorbed.DNA and RNA in the dermal elastin or collagen absorb all UV radiations that reach the dermis.Subsequently,inflammatory damage occurs in the epidermis and dermis;thus, DNA is the most likely target of inflammation damage.10There is also an increase in the expressions of nuclear transcription factors and cytokines,leading to an increase in ILs and inflammatory mediators in both serum and the epidermis, as well as osmosis of neutrophils and monocytes.11

After being exposed to UVB at a dose of 86, 215, and 400mJ/cm2for 48hours or 72hours,the back skin of mice develop erythema, which becomes more obvious over time.12Exposure to a 100mJ/cm2dose of UVB three times a week for 10weeks leads to an increase in the epidermal thickness of mice,with the proliferation of epidermal cells and infiltration of dermal neutrophils.13Celaet al.14exposed hairless mice to a 400mJ/cm2dose of solar UV rays(sUVR,280–370nm)and observed the skin at 24h or 192h post-irradiation.14This sUVR exposure caused the deep dermis to be infiltrated with macrophages and histiocytes, and caused the accumulation of neutrophils.These manifestations were more obvious at 192hours than 24hours post-irradiation.

Accurate animal models are crucial for the study of diseases.In vivostudies of UISI have mainly been performed using a mouse model.Table 1 describes the key components of the UISI mouse models used in previous studies, including the mouse strain, UV wavelength,exposure doses, irradiation scheme, phenotype, and molecular changes.

Current mouse models of UISI exhibit the following features.(1) The main irradiated waves are broadband UVB.Exposure to UVB plus UVA in the proportions that simulate the constitution of solar light has been utilized in a small number of studies.In general, UVC exposure has been avoided in previous studies.(2) The irradiation scheme comprises two types:single exposure and repeated exposure.High doses of irradiation are used in single exposure models.Constant low doses or increasing doses from a low dose are used in repeated exposure models.(3)The mice show similar phenotypes (skin erythema and swelling)in both acute and chronic UV-challenged mouse models.The histological features are epidermal proliferation and inflammatory cell infiltration (mainly neutrophils).15–18Moreover, the upregulation of cytokines and inflammatory mediators such as IL-6, TNF-α, and Cyclooxygenase-2 (COX-2) are key molecular markers.Chronic exposure models show an increased risk of photocarcinogenesis (see Section Inflammation and UVinduced tumorigenesis).

Molecular mechanisms in UISI

Previous studies have demonstrated that the classic inflammatory pathways involving NF-κB and TLR signals contribute to the mechanism of UISI.

NF-κB signal pathway

The NF-κB signal pathway mediates the synthesis of cytokines,such as IL-6, IL-8, and TNF-α,and serves as a crucial pathway in the regulation of inflammation.19The NF-κB protein family contains p50,p65,RelB,and c-Rel.Except for RelB,the other members of the NF-κB protein family combine with each other to make dimers,of which the most stable dimer is the combination of p50 or p52 with p65.When combined with the inhibiting factor IκB,NF-κB proteins exist in their inactive forms in cells.IκB includes four subtypes,κBα,IκBβ,IκBγ,and IκBε.When the NF-κB signal is activated, IκB is phosphorylated and degraded, leading to the nuclear translocation of NF-κB.Among the subtypes of IκB,IκBα is related to the transient activation of NF-κB,while IκBβ is related to the persistent activation of NF-κB.The phosphorylation of IκB needs the participation of IκB kinase.20

Pratheeshkumaret al.13demonstrated that exposure to UVB increased the protein level of IκB kinase in mice skin lysis buffer, causing the degradation of IκBα and the translocation of p65 into the nucleus.After exposure to a gradually increasing dose (36–108mJ/cm2) of UVB three times per week for 10weeks, the skin of the mice was erythematous and showed an increase in thickness.An immunohistochemistry study showed increases in IL-6,COX-2, and NF-κB/p50 in skin after UVB exposure.6Divyaet al.7reported that the level of NF-κB/p65 was decreased in the cytoplasm and increased in the nuclei in epidermal skin after exposure to 100mJ/cm2of UVB three times per week for 10weeks.Immunohistochemistry study showed that the expressions of NF-κB,TNF-α,and COX-2 were upregulated in the skin after UVB exposure.The protein levels of TNF-α and COX-2 were increased in skin lysate.

TLR-mediated signal pathway

TLR plays an important role in the regulation of innate immunity.15Exposure to a single high dose of UVR(400 mJ/cm2) caused a marked decrease in the transcriptional levels of TLR2 and TLR4.However,repeated low doses of UV radiation actually led to the increased transcription of TLR2 and TLR4.14Compared with wild type(WT)mice,TLR2 knockout mice showed less erythema and scale after exposure to chronic sUVR(a dose of up to 250mJ/cm2in the telogen period and 400mJ/cm2in the anagen period three times daily for 6weeks).TLR2 knockout mice showed a low level of increase in epidermal thickness and the production of IL-1α and IL-6, as well as lesser neutrophil infiltration in comparison to WT mice after exposure to sUVR.15Taken together,these findings show that the TLR pathway contributes to the process of UISI.Besides the classic inflammatory signal pathways involving NF-κB and TLR,recent evidence has uncovered some new inflammation related molecules involved in the process of UISI.

IL receptors

Molecular mark IL-6, TNF-α COX-2, TNF-α, p-ERK1/2, p-p38,p-JNK1/2, p-MKK4, NF-κB IL-6, COX-2, NF-κB IL-6, TNF-α , COX-2 IL-1β, IL-6, TLR2 COX-2 IL-6, TNF-α, COX-2 IL-6, TNF-α IL-1β, IL-6, CCL5 (epidermis)Skin phenotype Increased epidermal thickness, Dermal neutrophil infiltration (high)Increased epidermal thickness, epidermal hyperplasia, Dermal neutrophil infiltration Increased epidermal thickness, epidermal hyperplasia, Dermal neutrophil infiltration Increased transepidermal water loss, epidermal redness, increased epidermal thickness Increased epidermal thickness, epidermal dyskeratosis, acanthosis,Dermal neutrophil infiltration Sun burn cells in epidermis,hyperplasia, increased skin thickness Epidermal redness, neutrophil infiltration Epidermal redness, increased epidermal thickness Dermal macrophage infiltration Irradiation scheme Single (high)Once a day for 4 days (low)3/w, for 10 w 3/w, for 10 w 3/w, for 10 w 3/w, for 6 w Once a day for 23 days Single Single Single 3/w, for 10 w Single dose(mJ/cm2)400 (high)20 (low)100 100 36 (1 w); 54 (2–4 w); 72(5–6 w); 108 (8–10 w)75–250 (anagen period);75–400 (telogen period)80 (1–11 days);220(12–23 days)86;215;430 200 120 (acute)70 (chronic)Wave length or constitution 20%–30% UVA +70%–80% UVB UVB UVB UVB 275–380 nm UVB UVB UVB UVB Sample Skin skin Skin skin skin skin skin,epidermis SKH-1 hairless Foxn1nu/CrlNarl Strain of mice SKH-1 hairless Cela et al.14SKH1-hrBR Skin Bl6-SV129 skin Table 1 Mouse models of UV-induced skin inflammation.Reference Pratheeshkumar et al.13 BALB/cAnN.Cg-Divya et al.7 Wu et al.6 Park et al.15C57/BL6 Singh et al.16Hsd:ICR(CD-1R)Ryser et al.12C57BL/6×129 Lee et al.17C57BL/6J Degueurce et al.18SKH1-C57/IL: interleukin; NF-κB: nuclear factor kappa-B;TLR2: toll-like receptor 2;TNF-α: tumor necrosis factor-α; w: week; UV: ultraviolet.

After exposure to UVB,HaCaT cells and human primary keratinocytes show increased secretion of IL-22R, IL-1α,IL-6,and IL-18.Similarly,after exposure to a 100mJ/cm2dose of UVB five times per week for a total of 13weeks,immunochemistry shows that the expression of IL-22R in the skin of mice is upregulated.One study irradiated 30 male volunteers aged 19–85years with 10mJ/cm2of UVB on their buttocks.21At 24h after exposure, skin samples were taken from irradiated and unirradiated areas.In the skin samples exposed to UVB,the protein level of IL-22R was extremely increased compared with the unexposed skin samples.

Cluster of differentiation

Singhet al.16exposed mice to UVB radiation every 2days for 23days at a dose of 80mJ/cm2for the first 11days and 220mJ/cm2from day 12 to 23.The skin thickness of the mice was increased after irradiation,and the mRNA levels of IL-6,IL-10, IL-17A, and COX-2 were increased in the lysate of whole skin samples.Intraperitoneal injection with small interfering RNA (siRNA) to interfere with CD28 mRNA inhibited the UVB-induced increases in skin thickness and the mRNA levels of IL-6, IL-10, IL-17A,and COX-2.

Ryseret al.12exposed CD1d knockout (CD1d-/-) and WT mice to 86,215,430mJ/cm2doses of UVB radiation.At 48hours and 72ours after exposure, both groups showed necrotizing scabs and erythema, with the skin manifestation aggravated in a time- and radiation dosedependent manner.Erosions and ulcers were also observed in severe cases;neutrophil infiltration was observed in the skin of the mice with these phenotypes of skin inflammation.In comparison to WT mice, these inflammation phenotypes were less frequent in CD1d-/-mice.After exposure to UVB, both CD1d-/-and WT mice exhibited increases in the mRNA levels ofIL-6, TNF-α, COX-2,CXCL-1, CXCL-2, andCCL3.However, the increases in the levels of these cytokines and mediators were less in WT mice.

Serum proteins related to inflammation

Serum amyloid A1 (SAA1) is an acute phase protein mainly produced in the liver.The serum level of SAA1 can rise 1000-fold in 24hours under acute stimulation due to inflammation, infection, and trauma.22-23Hanet al.24found that the mice skin showed erythema and swelling after subcutaneous injection of recombinant SAA1, and the mRNA and protein levels of IL-1α and IL-6 were upregulated.Similarly,after incubation with recombinant SAA1, normal human dermal fibroblasts (NHDFs)exhibited an increase in the mRNA levels of IL-1β, IL-6,and IL-8,as well as the protein levels of IL-6 and IL-8.The increased protein level of NF-κB/p65 was also observed.Transfection with TLR4 siRNA or treatment with NF-κB inhibitor BAY 11-7082 inhibited the increases of IL-1α, IL-6, and IL-8 in mRNA and protein levels in recombinant SAA1-treated NHDFs.These findings indicated that SAA1 contributes to the UISI through the TLR4 and NF-κB signal pathways.

Endogenous hormones

Yoonet al.25reported that endogenous estrogen can enhance UISI.They found that ovariectomized mice showed less skin swelling and lower protein levels of IL-1α,IL-6,and TNF-α than normal mice after exposure to sUVR at a single dose of 200mJ/cm2.The protein levels of these cytokines increased again after subcutaneous injection of endogenous estrogen.

Melatonin is a compound synthesized and secreted by the pineal gland.Kleszczy′nskiet al.26performed anin vitrostudy using cultured normal skin tissues.They found that the mRNA and protein levels of heat shock protein 70(Hsp70)increased significantly after irradiation.Transfection with Hsp70 siRNA led to the aggravation of the sUVR-induced decrease in IκBα mRNA in keratinocytes.In addition, the mRNA levels of IL-1β and IL-6 were further increased after sUVR exposure.Co-incubation with melatonin blocked these changes in the mRNA.Taken together, melatonin inhibited the sUVR-induced upregulation of Hsp70,and thus inhibited the activation of the NF-κB signal pathway and the responses of IL-1β and IL-6 after sUVR exposure.

Peroxisome proliferator activated receptor β/δ(PPARβ/δ) is a nuclear hormone receptor that plays an important role in regulating the differentiation of keratinocytes and lipid synthesis.27The coding gene of PPARβ/δ isPPAR Delta(Ppard).The miRNA MiR-21-3p can be activated by PPARβ/δ.Degueurceet al.18found that the levels of TGFβ1 mRNA and miR-21-3p were increased after UVB exposure in the epidermis of WT mice but not Ppard-/--mice.Injection with PPARβ/δ blocker GSK0660 and TGFβ1 blocker SB431542 in the back of WT mice inhibited the UVB-induced increase in miR-21-3p.After incubation with recombinant human TGFβ1,the miR-21-3p level was increased in HaCaT cells.After exposure to UVB, the mRNA levels ofIL-1α,IL-6, andCCL5in the epidermis were upregulated in WT mice but not in Ppard-/-mice.The mRNA levels of IL-1α, IL-6, and CCL5 were increased in HaCaT cells transfected with a miR-21-3p mimic.Moreover, Degueurceet al.18confirmed that the mRNA levels ofIL-1α andIL-6in the epidermis were increased after exposure to UVB.Injection of miR-21-3p inhibitor inhibited the UVB-induced increases inIL-6andIL-1α mRNA in the human skin explants, but did not affectTGF Symbol 1mRNA.Therefore,after the skin was stimulated by UVB, upregulated PPARβ/δ caused an increase in TGFβ1, eventually leading to an increase in miR-21-3p and the production of inflammatory cytokines.

Enzymes

Isocitrate dehydrogenase 2 (Idh2) is a key enzyme in mitochondrial redox reactions.Kuet al.28found that 20mJ/cm2of UVB caused a significant increase in the epidermal and dermal thicknesses in Idh2-/-mice but not in WT mice.Notch and ΔNp63 are key proteins in epidermal growth and regeneration.Notch is an antagonist of ΔNp63,and their balance maintains the steady state of the epidermis.Compared with WT mice, Idh2-/-mice had a higher protein level of Notch but a lower protein level of ΔNp63.After exposure to UVB, there were increases in CD11b+and Ly6c+cells in the skin tissue of Idh2-/-mice,indicating an increase in the concentration of monocytes,which wasconfirmed as mast cells in dermis.Inaddition,the protein levels of TNF-α and induced nitrogen monoxide synthase were increased significantly in peripheral blood.Therefore,the Idh2-/-mice exhibited more marked inflammation after UVB irradiation than the WT mice, which might be influenced by the downregulation of ΔNp63.

Transglutaminase (TG) is an enzyme family that catalyzes the Ca2+-dependent post-translational modification of proteins.TG2 is one member of this protein family,and increased TG2 activity is often detected in tissues with inflammation.29Leeet al.17reported that UVB increased TG2 activity in HaCaT cells.After exposure to 200mJ/cm2of UVB,TG2-deficient mice showed less skin erythema and swelling, and less macrophage infiltration in skin tissue compared with WT mice.Exposure to UVB caused lower increases in IL-6 and TNF-α secretion and mRNA levels in HaCaT cells withTG2gene knockout than in HaCaT cells withoutTG2gene editing.After exposure to 10 mJ/cm2of UVB,activation of the PLC-IP3/DAG pathway contributed to the promotion of Ca2+release from endoplasmic reticulum and TG2 activation.Moreover, TG2 enhanced the phosphorylation of NF-κB/p65, and the increases inIL-6, IL-8, andTNF-α transcription.

Genetic mutations related to phenotypic abnormalities of UV-induced skin inflammation

Kindlin-1 is a cytoskeletal protein coding byfermitin family member 1.The mutation ofkindlin 1, including deletion, insertion, nonsense mutation, and splicing, can lead to Kindler syndrome (KSKs).The early stage of the disease is marked by increased skin fragility,pigmentation,and photosensitivity, and the later stage can progress to irreversible tissue damage, atrophy, and scarring of the skin and mucous membranes.In patients with KSKs,heterochromia often appears first in exposed skin areas,such as the face and hands.Immunohistochemistry study showed higher levels of IL-1α,IL-6,TNF-α,and COX-2 in these skin lesions.Compared with normal human keratinocytes (NHKs), the UVB-induced increase in IL-1α expression and secretion was more significant in keratinocyte cells from patients with KSKs(approximately 7pg/ng proteins in KSKsvs.2pg/ng in NHKs).The phosphorylated level of p38 was higher in KSKs than in NHKs.Overexpression of kindlin-1 in KSKs inhibited the UVB-induced increase in p38 phosphorylation,indicating that the mutation ofkindlin-1is related to the UVBinduced increase in p38 phosphorylation.Furthermore,the special p38 inhibitor SB203580 inhibited the increases inIL-1α,IL-6, andTNF-α mRNA levels.In KSKs, the reactive oxygen species level was increased after UVB exposure, and this increase was inhibited by antioxidant 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (trolox).In addition, trolox inhibited the increase in UVB-induced p38 phosphorylation.30

Nutrition metabolism

Zhuet al.8exposed mice to UVB at a dose of 250mJ/cm2three times per week for 4weeks.In comparison with mice fed a normal diet, mice fed a selenium-deficient diet had higher levels of p38 phosphorylation and JNK protein in skin lysate,as well as higher levels ofIL-1α,IL-6,TNF-αCOX-2,and induced nitrogen monoxide synthase mRNA.These findings indicate that a selenium-deficient diet aggravates the phenotype of UISI.

UISI in skin disorders

Photo-aging

Persistent inflammation and oxidative stress both contribute to extrinsic skin aging.Karthikeyanet al.31exposed mice to 10J/cm2of UVA per day for 10days to create a model of photo-aging.Higher mRNA levels of matrix metalloproteinase(MMP)-13andMMP-9were observed.Immunohistochemistry studies indicated that UVA radiation reduced dermal collagen density and induced MMP-2 in the mice.Increased levels of IL-6,TNF-α,and COX-2,and more nuclear translocation of NF-κB/p65 were also observed, which demonstrated the activation of inflammation.Zhanet al.32observed an increased thickness of the epidermis and increased expressions of MMP-1 and MMP-3 in a mouse photoaging model.The inflammatory cytokines IL-1α,IL-6,IL-10,and TNF-α were increased in skin homogenate in this model.These studies indicate a close relationship between UISI and photo-aging.

Chronic actinic dermatitis

Chronic actinic dermatitis is a common clinical photosensitive disease that is closely related to UISI.Leiet al.33found that among 65,091 mRNAs, 4,401 mRNA in patients with chronic actinic dermatitis had different expression from those in healthy people.Among the top ten genes with the most significant expression differences,TNFAIP3andDEFB4Aare considered to be associated with the inflammatory response.Compared with healthy people, theTNFAIP3mRNA level in the skin lesions of patients with chronic actinic dermatitis was significantly decreased, while theDEFB4AmRNA level was significantly increased.33TNFAIP3 has an inhibitory effect on the NF-κB pathway,and its downregulation contributes to an increase in NF-κB activity.34

Inflammation and UV-induced tumorigenesis

UV-induced inflammation is thought to be an important cause of non-melanocytic skin cancers,including basal cell and squamous cell carcinomas.12

Autophagy plays an important role in maintaining the stability of organisms.Autophagy-related gene 7 (ATG7)is a key gene in the autophagy machinery.Qianget al.35constructed acute and chronic UVB exposure mouse models by exposing mouse to 100mJ/cm2of UVB once every other day for three times in total (acute model) or three times per week for 27weeks (chronic model).The acute inflammatory response induced by UVB was weaker inATG7epidermal conditional knockout(cKO)mice than in WT mice.In addition, in the chronic UVB exposure model,skin tumors began to occur at week 14 in WT mice,but did not appear until week 26 inATG7cKO mice.At week 27, theATG7cKO mice had significantly fewer tumors than WT mice.In WT mice exposed to acute or chronic UVB radiation, the dermis showed infiltration of macrophages,neutrophils,and mast cells.However,these histological features were not seen in theATG7cKO mice.Cytokine microarray analysis showed that acute UVB radiation increased the secretions of IL-1β,IL-6,CXCL1,CXCL2, CCL2, CCL3, CSF3, and TREM1 in WT mice,while chronic radiation increased the secretions of IL-1β,CXCL1,CXCL2,CCL3,CSF3,and TREM1 in WT mice.In contrast,theATG7cKO mice did not show increases in these cytokines after either acute or chronic exposure to UVB.These findings demonstrate that UVB radiationinduced skin inflammation promotes the occurrence of tumors, and that the autophagy key geneATG7plays a key role in this mechanism.

Baldet al.36constructed a mouse model of melanoma by topically applying 7,12-dimethylbenz(a)anthracene(DMBA)on the backs of mice.On days 7,10,14,17,98,and 102 after the application of DMBA,mice bearing serial melanoma skin transplantswere exposed to 4,500mJ/cm2of UVB.Although UVB exposure did not affect the number,incidence,and diversity of DMBA-induced melanoma,mice exposed to UVB showed a higher rate of lungmetastasis than control mice.Melanocytes were seen around dermal vascular endothelial cells in four of the 20 UVB-challenged mice while none was seen in control ones.This vascular growth pattern is observed in about one-fifth of human patients with melanoma,and is considered an early sign of metastasis and an indicator of poor prognosis.Baldet al.36also found that UVB-induced phenotypes, including epidermal hyperplasia, neutrophil infiltration, and angiogenesis,were weakerin TLR4 orMyd88knockout(TLR4-/-,Myd88-/-) mice than in WT mice.In the TLR4-/-or Myd88-/-mice, the UVB-induced increases in melanocyte vascular growth and spontaneous lung metastasis were also completely eliminated.Antibody-mediated depletion experiments validated the key role of Ly6G+neutrophils in this process.Their study indicates that neutrophil-associated inflammation induced by TLR4/Myd88 might play a role in promoting vascular growth and spontaneous pulmonary metastasis in patients with melanoma.

Conclusion

In summary, UISI is a crucial mechanism in the series of biological events that occur in skin damage caused by acute or chronic UV radiation.However,the process and mechanism of UISI need to be elucidated.The limited understanding of the process and regulatory mechanism of UISI hinders our elucidation of the mechanism of the occurrence and development of UV-related skin diseases.

The first key question that needs to be answered is whether UISI has a special regulatory mechanism in inflammatory modulation.According to current evidence,the activation of classic inflammatory regulatory pathways, including NF-κB and TLR, and increases in cytokines and inflammatory mediators such as IL-1α,IL-6, TNF-α, and COX-2 are commonly observed in different investigatory settings.However, these are the general indicators of the inflammatory process.More specific markers of UISI need to be defined.Interestingly,Kimet al.21found that IL-22Rα might contribute to UISI,suggesting the complexity of UV-induced reactions between cytokines and their receptors.Multi-omics technology should be utilized to clarify the regulated profiling of inflammatory cytokines and mediators in response to the different doses and levels of accumulation in UV radiation.Furthermore, the source cells of these cytokines and inflammatory mediators remain unclear.It was previously thought that T cells, macrophages, or neutrophils could all be recruited and contributed to the inflammatory process of UISI.However,the actual role of these immune cells, as well as keratinocytes and dermal fibroblasts with immunomodulatory effects, in the initiation and progression of UISI has not been uncovered.Multiple signaling pathways are involved in inflammatory regulation.However,the crucial pathways associated with inflammatory regulation in UISI need to be explored.Investigation into the special profiling of cytokines and mediators will elucidate the core regulatory pathways associated with UISI.Comparative investigations between UISI in various UV-related skin diseases versus other characteristic types of inflammation in skin disorders such as psoriasis, atopic dermatitis, and autoimmune diseases should be encouraged.The identification of specific and general inflammatory features is an essential step in clarifying the biological roles and contribution of UISI in UV-related or UV-aggravated skin disorders.To obtain more high-quality real-world data, researchers need to conduct clinical studies aimed at elucidating the occurrence and development characteristics of UV-related skin diseases.

Another key question in the investigation of UISI is how to construct animal models that closely mimic real UVrelated skin disorders.In the currently available studies,mice with acute or chronic exposure to special bands of UV radiation were the most common models.Table 1 lists the methodological elements of model construction in previous studies.To mimic UV exposure under natural conditions as closely as possible,the combination of UVA and UVB radiation that simulates the components of solar UV light should be promoted.However, the current models were UV skin damage models rather than precise or pure UISI models, as the biological effects of UV radiation involve multiple target mechanisms, such as inflammation,cell death,aging,DNA damage and repair,and oxidative stress reaction.The acquisition of more data from clinical disease research into UV-related disease will enable researchers to conduct more comparative medical studies to establish more precise animal models.

As one of the important mechanisms in UV-challenged skin, the process and modulation of UISI needs to be investigated in the future.In particular,the special profiles of cytokines and inflammatory mediators and the core regulatory pathways should be identified clearly.These investigations would be promoted rapidly, accompanied by high-quality clinical research studies being conducted on patients with UV-related skin diseases and precise animal models of UISI being constructed.

Acknowledgments

This work was supported by CAMS Innovation Fund for Medical Sciences(Nos.2016-I2M-1-005,2017-I2M-1-017),the Nanjing Incubation Program for National Clinical Research Center(Nos.2019060001).