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Department of Dermatology, West China Hospital, Sichuan University, Chengdu, ChinaInstitute of Dermatology and Venereology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology, Chengdu, China
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu, China
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, ChinaLaboratory of Dermatology, Clinical Institute of Inflammation and Immunology (CIII), Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
The subjective symptoms of rosacea are complex and affect patients’ quality of life.
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Pruritus of rosacea is not purely due to burning, stinging sensations.
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Temperature changes play an important role in the onset of pruritus.
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LL-37 intradermally injected on the face of mice could evoke lesions and scratches.
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The TRPV4 and TRPM8 are related to the pruritus of rosacea.
Abstract
Background
Certain sensations are the secondary phenotypes of rosacea and affect patients’ quality of life. Transient receptor potential (TRP) channels may be involved in its occurrence. However, there is a lack of research independently discussing itch in rosacea.
Objectives
Our study aimed to investigate risk factors for pruritus in rosacea patients and to discover the molecular mechanism of pruritus.
Methods
A binary logistic regression model was used to identify significant variables affecting pruritus in 782 rosacea patients. The LL-37 was injected intradermally into the face of mice to establish the animal model. qRT–PCR, immunohistochemistry and immunofluorescence were used to analyse the expression differences in pruritus-related molecules in mouse skin and the corresponding trigeminal ganglion (TG) between pruritus and nonpruritus groups.
Results
The incidence of pruritus in rosacea was 42.46%, and the incidence of other symptoms increased with pruritus. Temperature effects were prominently related to the itch sensation of rosacea. Intradermal injection of LL-37 not only caused rosacea-like facial lesions but also induced a behavioural pattern indicative of pruritus. Increased expression of the temperature-sensitive receptors TRPV4 and TRPM8 was found in pruritic mouse skin and TG and human skin samples.
Conclusions
In rosacea patients, pruritus occurs frequently along with burning, flushing and sensitivity, most likely due to changes in temperature. The temperature-sensitive receptors TRPV4 and TRPM8 are both involved in the mechanism of pruritus in rosacea.
Rosacea is a chronic cutaneous disorder characterized by transient or persistent erythema, telangiectasia, papules and pustules, primarily affecting the central face. Rosacea is frequently accompanied by discomfort, including burning, stinging and itching [
]. According to clinical observations, itch is an unpleasant sensation bothering a certain proportion of patients with rosacea, profoundly impairing the overall quality of life [
]. Current evidence suggests that there are two major categories of itch receptors, namely, G protein–coupled receptors and transient receptor potential (TRP) channels [
]. Moreover, LL-37 can increase TRPV4 expression directly, which is a necessary condition for the degranulation of mast cells and participates in the inflammation of rosacea [
]. The activation of TRPV1 and TRPA1 also causes the release of important mediators of sensory pathologies and neurogenic inflammation, including substance P and calcitonin gene-related peptide, which are also implicated in the pathogenesis of rosacea [
]. TRPV4 can be activated by heat, inflammatory metabolites and osmotic stress, while TRPA1 and TRP melastatin 8 (TRPM8) can be activated by cold and menthol [
]. Because itch-related TRP channels are also implicated in the pathogenesis of rosacea, these receptors may play a role in the itch sensation of this condition as sensors for certain triggering factors [
]. However, little evidence has been provided to elucidate the potential role of these receptors in itch in rosacea, presumably due to the lack of clinical data and appropriate in vivo models.
The aetiology and pathogenesis of itch in rosacea patients remain to be elucidated to further alleviate this unpleasant sensation. Therefore, the aim of this study was to (1) identify the potential triggering factors of itch sensation in rosacea patients by a logistic regression model; (2) model facial pruritus in rosacea-like mice by LL-37 injection; (3) investigate the potential role of specific channels and receptors in itch in rosacea by real-time quantitative polymerase chain reaction (qRT–PCR), immunohistochemistry and immunofluorescence; and (4) analyse staining results by semiquantitative analysis. Cathelicidin LL-37 (Cath LL-37) was used to successfully model rosacea-like lesions [
Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and ll-37 on histamine release and prostaglandin d(2) production from mast cells.
]. Therefore, we injected LL-37 into the facial skin of mice. Finally, we successfully simulated the rosacea-like rash and observed patterns of behaviour indicating pruritus. Then, we found that the expression of TRPV4 and TRPM8 was significantly upregulated in the skin tissues of pruritus mice and rosacea patients compared with those of nonpruritus mice. As critical sensors for heat and cold, respectively, the overexpression of TRPV4 and TRPM8 in rosacea patients with pruritus may explain the involvement of thermal factors in itch sensation suggested by our clinical observations.
2. Materials and methods
2.1 Patients and statistics
A total of 782 patients with a diagnosis of rosacea [
] between October 10th, 2019, and August 31st, 2021, were recruited in our study and divided into two groups based on whether they had rosacea lesion itch. Those patients with other pruritic skin diseases on the face were excluded. Demographic and clinical characteristics, including diet and skin care habits and potential risk factors, were compared between the two groups. Variables with P < 0.1 were included in the binary logistic regression model. Univariate analysis was used to compare the variables, and these significant variables or those considered clinically influential were analysed by multivariate stepwise logistic regression (backwards stepwise logistic regression) to identify significant factors implicated in pruritus in rosacea patients. The statistical analysis was performed using SPSS version 23.0. All the clinical data and specimens were approved by Sichuan University in Chengdu, China (Protocol 2019–248).
2.2 Animal behavioural studies
Seven-week-old female BALB/c mice purchased from Hunan Silaike Jingda laboratory Animal Co., Ltd. (Hunan, China) were randomly divided into two groups: the PBS group (n = 18) and the LL-37 group (n = 18). All animal experiments were approved by the Animal Ethics Committee of the Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital (Protocol 2021–246). LL-37 peptide was synthesized by CS Bio Co., Ltd (Shanghai, China) and dissolved in phosphate-buffered saline (PBS). The intradermal injection in the mouse cheek was performed as previously described [
]. For behavioural tests, animals were habituated to separate, clear, plastic containers at least 2 days before observation. Twelve hours after the last injection, their behaviors were separately videoed in the containers for at least 30 min. Behavior and lesion assessments were performed by observers blinded to thegrouping. The hind paws lifted from the floor and scratched the rash, then placed on the floor or in the mouth to count as a bout of scratching [
]. The detailed process is shown in a flowchart (Figure A). The pruritus (LL-37) group was defined by significantly more than eight itching bouts, which was the maximum in the PBS group. Statistics for this part of the study were performed by GraphPad Prism 7.04 (GraphPad Software Inc., CA, USA).
2.3 Quantitative RT–PCR
Total RNA was extracted from skin or TG samples using a FastPure Cell/Tissue Total RNA Isolation Kit V2 (Vazyme Cat., Nanjing, China). cDNA was synthesized from 1000 ng of total RNA by a Prime ScriptTM RT Reagent Kit with gDNA Eraser (Perfect Real Time) purchased from Takara Biomedical Technology Co., Ltd. (Beijing, China). Each skin cDNA sample was amplified for 15 genes related to itching and TNF-α and IL-1β related to rosacea inflammation. TG cDNA samples were amplified for genes related to itching only.
Reactions were performed in a 20 µl reaction volume using TB Green Premix Ex TaqⅡ (Tli RNaseH Plus) (Takara Biomedical Technology Co., Ltd, Beijing, China) and ABI QuantStudio 6 Flex (Thermo Fisher Scientific, MA, USA). The real-time PCR conditions were 95 °C for 30 s followed by 40 cycles at 95 °C for 5 s and 60 °C for 34 s. The mRNA levels of all genes were normalized to GAPDH and calculated using the 2-△△CT method. The comparisons were performed using a t-test by SPSS version 23.0. and P value < 0.05 was considered statistically significant. The primer sequences (5′ to 3′) involved are shown in Supplementary Table B.
2.4 Immunohistochemistry
Tissues were treated with EDTA pH 9.0 (ZSGB Bio, Beijing, China) for antigen retrieval and then incubated with primary antibodies against TRPV4 (catalogue No. 20987–1-AP, dilution 1:200, Proteintech) and TRPM8 (catalogue No. 12813–1-AP, dilution 1:200, Proteintech) overnight at 4 °C. Then, tissues were incubated with goat anti-rabbit secondary antibody (catalogue No. ZB-2301, dilution 1:250, ZSGB Bio) for 40 min at room temperature. Images were captured using NIS-Elements AR (Nikon, Japan) and analysed by ImageJ analysis software (NIH, USA) with IHC Profiler Plugin. Five nonoverlapping, random fields for the skin (×400 total magnification) and 3 for the TG of each mouse were examined. The region of interest (ROI) of skin tissue was in the epidermis.
2.5 Immunofluorescence
We used anti-Mast Cell Tryptase staining to detect mast cell activation. Tissues were treated with citric acid (ZSGB Bio, Beijing, China) for antigen retrieval and then incubated with primary antibody against Tryptase of Mast Cell (catalog No. ab2378, dilution 1:2000, Abcam) overnight at 4 °C. Then, tissues were incubated with Alexa Fluor® 488 AffiniPure goat anti-mouse IgG (H+L) secondary antibody (catalog No. 111–485–003, dilution 1:200, Jackson) for 40 min at room temperature. TRPV4 and TRPM8 were double stained. After antigen repair, tissues were incubated with primary antibody against TRPV4 (catalog No. 20987–1-AP, dilution 1:200, Proteintech) overnight and washed four times after incubation with Alexa Fluor® 488 AffiniPure goat anti-rabbit IgG (H+L) secondary antibody (catalog No. 111–545–003, dilution 1:200, Jackson) for 40 min at room temperature. Then, tissues were incubated with TRPM8 primary antibody (catalog No. 12813–1-AP, dilution 1:200, Proteintech) overnight at 4 °C again. Finally, the secondary antibody CyTM3 AffiniPure Goat Anti-Rabbit IgG (H+L) (catalog No. 111–165–003, dilution 1:200, Jackson) was incubated with the tissue for 90 min. Images were captured using a Leica s-STELLARIS (Leica, Germany) and analyzed by ImageJ analysis software (NIH, USA).
3. Results
3.1 Population characteristics and pruritus-related risk factors
Of the 782 patients, 332 (42.46%) were assigned to the pruritus group, and 450 (57.54%) were assigned to the nonpruritus group according to their itching condition. The statistically significant variables are summarized in Table A. The results of logistic regression analysis assessing 6 potential risk factors are presented in Table 1 and Fig. 1a. Two of these 6 factors are related to temperature, including aggravation by both cold and heat (hot and cold biphase) and the seasons and their corresponding temperature change. The odds ratio (OR) values were 1.518 [95% confidence interval (CI) 1.019–2.263, P = 0.040] and 1.449 [95% confidence interval (CI) 1.023–2.054, P = 0.037], respectively. Statistical analysis was performed on concomitant clinical symptoms and signs (Fig. 1b). Nine of ten features in the pruritus group occurred significantly more often than in the nonpruritus group, with burning, flushing and sensitivity occurring in 72.89% (P < 0.001), 69.88% (P < 0.05) and 68.98% (P < 0.01) of patients in the pruritus group, respectively.
Table 1Univariate and Multivariate logistic regression assessing risk factors for pruritus in rosacea.
Fig. 1Six factors are implicated in itch sensation of rosacea patients and other accompanying symptoms. a. Forest plot showing 6 factors related to itch of rosacea, 2 of which are related to temperature changes. (* P﹤0.05, ** P﹤0.01, *** P﹤0.001 versus nonpruritus, Chi Square test). b. Other clinical features accompanied by itch (%= n/332), 9 of 10 rosacea symptoms were significantly increased in the pruritus group.
3.2 Construction of the LL-37-induced pruritus mouse model and erythema assessment
Inflammatory lesions were elicited by intradermal injections of LL-37 in cheek skin, and behavioural responses to pruritus were subsequently observed as the number of bouts (Fig. 2). The severity of the erythema of skin lesions was evaluated and compared between the PBS group and the LL-37 group, and significantly higher scores were found in the LL-37 group (P < 0.0001. Fig. 2b, Figure B). The frequency of bouts was generally higher in the LL-37 group (P < 0.01. Fig. 2c). Eight of eighteen (44.44%) mice injected with LL-37 were found to have pruritus according to the frequency of bouts, which was not significantly different from that in pruritus patients in our clinical data (42.46%, P = 0.866). However, there was no correlation between erythema severity scores and the number of bouts (P = 0.918. Fig. 2d).
Fig. 2More scratching bouts of mice were observed in the LL-37 group, and upregulated mRNA expression of TRPV4 and TRPM8 is shown in both skin tissues and trigeminal ganglia of pruritus mice. a. Representative histopathological H&E staining of skin lesions in the LL-37 group：thickened epidermis and increased inflammatory cell infiltration compared with the PBS group. b-c. Both erythema scores (b) and scratching bouts (c) of the LL-37 group were greater than those in the PBS group (**** P＜0.0001, ** P＜0.01). d. No significant correlation between the number of scratching bouts and erythema severity scores was found (P = 0.918). e. Five out of seventeen genes with differential expression in the skin tissues of pruritus mice（LL-37, n = 4）, nonpruritus mice（LL-37, n = 4）and control mice（PBS, n = 4）by real-time quantitative polymerase chain reaction (qRT–PCR) (** P＜0.01, # P＜0.05 and the expression in the nonpruritic group was higher). Interestingly, the expression of proinflammatory cytokines (TNF-α and IL-1β) was not upregulated in the skin tissues of pruritus mice compared with those of the nonpruritus. f. Differential expression of the genes of interest in the corresponding Trigeminal ganglion (TG) of three groups (n = 4 in each group) by qRT-PCR, (* P＜0.05).
3.3 Upregulated expression of TRPV4 and TRPM8 in the skin and trigeminal ganglia of pruritus mice
The expression levels of the 17 genes in skin biopsy samples were detected by qRT–PCR. The mRNA levels of TRPV4 (P < 0.01), TRPM8 (P < 0.01) and gastrin-releasing peptide (GRP) (P < 0.01) in pruritus mice were significantly increased compared with those in nonpruritus mice, as shown in Fig. 2e. Similar results were presented in trigeminal ganglia (TG) (P < 0.05. Fig. 2f). TNF-α and IL-1β, crucial cytokines implicated in the inflammation of rosacea, did not increase in the skin tissue of the pruritus group.
3.4 Increased expression of Mast Cell Tryptase, TRPV4 and TRPM8 were found in pruritus mice
The expression of Mast Cell Tryptase in the pruritus group was higher than that in the non-pruritus group and PBS group in immunofluorescence (Figure C). The distribution of TRPV4 and TRPM8 in the skin and TG of mice was observed by immunohistochemistry and immunofluorescence, as shown separately in Fig. 3a and Fig. 4a. The immunohistochemical results of the samples above both illustrated an increase in TRPV4 and TPRM8 colocalized to the membrane of epidermal cells. Epidermal TRPV4 and TRPM8 were rated semiquantitatively, which showed increased staining in pruritus skin versus nonpruritus skin (P < 0.05. Fig. 3b-d). Similar results were observed in TG, as shown in Fig. 4b-d. In conclusion, increased immunoreactivity of TRPV4 and TRPM8 was found in the skin and TG of mice in the pruritus group. However, double immunofluorescence revealed that the colocalization of TRPV4 and TRPM8 was not significantly observed in TG (Pearson's R value < 0.8, Fig. 4e-h).
Fig. 3The expression of TRPV4 and TRPM8 is upregulated in the skin tissues of pruritus mice versus nonpruritus mice. a. Localization and expression of TRPV4 and TRPM8 in the skin tissues from 3 groups by immunohistochemistry and immunofluorescence. Immunofluorescence: TRPV4 (488 nm, green), TRPM8 (550 nm, red) and nuclei DAPI (blue). Scale bares: 50 µm (×400 magnification). b-c. Quantification of TRPV4 (b) and TRPM8 (c) in the epidermis by immunohistochemistry (n = 3). The percentage contibution of positive was evaluated by Image J software, (**** P＜0.0001, ** P＜0.01). d. Quantification of TRPV4 and TRPM8 in the epidermis by immunofluorescence (n = 3). The integrated density (IntDen) was compared between 3 groups, (*** P＜0.001).
Fig. 4The expression of TRPV4 and TRPM8 is upregulated in Trigeminal ganglia (TG) in the corresponding lesions of pruritus mice versus nonpruritus mice. a. Localization and expression of TRPV4 and TRPM8 in TG of three groups by immunohistochemistry and immunofluorescence. Scale bares: 50 µm (×400 magnification) for immunohistochemistry, 10 µm (×400 magnification) for immunofluorescence. b-c. Quantification of TRPV4(b) and TRPM8(c) in the TG tissue by immunohistochemistry (n = 3). The percentage contibution of positive was evaluated by Image J software, (**** P＜0.0001, * P＜0.05). d. Quantification of TRPV4 and TRPM8 in the corresponding TG samples by immunofluorescence (n = 3). The integrated density (IntDen) was compared between 3 groups (**** P＜0.0001, *** P＜0.001). e. Colocalization of TRPV4 and TRPM8 in TG of pruritus mice by immunofluorescence. Orange circles show the areas where TRPV4 and TRPM8 are colocalized. f-h: Colocalization expression analysis of TRPV4 and TRPM8 by immunofluorescence in image TG1 (f), TG2 (g) and TG3(h) respectively from 3 pruritus specimens. The Pearson’s R value were 0.70, 0.60 and 0.71 respectively.
3.5 Upregulation of TRPV4 and TRPM8 expression in the skin lesions of rosacea patients with pruritus
A set of immunofluorescence stained skin biopsy samples from pruritus and nonpruritus rosacea patients, as well as healthy controls, is shown in Fig. 5a. Immunofluorescent staining of human skin successfully labelled TRPV4 and TRPM8 in the epidermis. It showed that the fluorescence of TRPV4 and TRPM8 antibodies was obviously enhanced in the epidermal cell membrane of pruritus patients, compared with nonpruritus patients and the healthy population. An increased intensity of epidermal staining was shown by semiquantitative analysis (P < 0.01, Fig. 5b).
Fig. 5The expression of TRPV4 and TRPM8 is significantly upregulated in skin lesions of pruritus rosacea patients versus nonpruritus patients. a. Localization and expression of TRPV4 and TRPM8 in skin lesions of pruritus patients, nonpruritus rosacea patients and healthy controls by immunofluorescence. Scale bares: 50 µm (×400 magnification). b. Quantification of TRPV4 and TRPM8 in the epidermis of human skin tissues by immunofluorescence (n = 3). The integrated density (IntDen) was evaluated by Image J software (** P＜0.01, * P＜0.05).
]. According to our clinical observations, 42.46% of rosacea patients complained of pruritus, which was consistent with our animal experiment results that 44.44% of mice displayed scratching behaviour due to pruritus elicited by LL-37. Through the comparison of the two clinical groups with and without pruritus, our results supported the previous findings that certain factors can elicit the occurrence of itch, such as dryness [
], ultraviolet radiation and factors related to hot and cold temperatures. The simultaneous effects of cold and heat can aggravate itching, which often occurs in spring and autumn. However, the severity of the disease was not among these factors, which was also confirmed later by the animal model. The classical inflammatory factor TNF-α did not increase in the pruritus group, while IL-1β was even higher in the non-pruritus group. It seems that pruritus is not associated with inflammatory conditions or the erythema severity of rosacea, as mentioned before [
]. Nevertheless, 2 of the 6 factors are related to temperature, indicating the importance of temperature changes, cold and heat in the pathogenesis of pruritus in rosacea.
It was previously known that itching was not only a symptom of a disease, but the result of interaction between the skin, ganglia, and brain regarding the immune and nervous systems [
]. In our study, other pruritic skin disorders were also found to be a risk factor of itching. Additionally, both our research and previous studies have shown that itching is not always an independent feeling, which was embodied in the fact that patients with pruritus are often accompanied by burning, prickling, and stinging [
]. The complexity of rosacea pruritus may be an important reason for the lack of previous research.
Another reason for the rarity of research on subjective symptoms of rosacea is the lack of animal models. LL-37 is an antibacterial peptide produced by epithelial tissue against damage, ultraviolet rays, and pathogenic microorganisms [
Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and ll-37 on histamine release and prostaglandin d(2) production from mast cells.
]. In our study, we found that LL-37 did not cause an increase in IL-31 in the mouse skin. However, the expression of Trpytase, a marker of mast cell activation [
], increased in the pruritus group. This suggests that LL-37 may cause itching behavior through mast cell activation. However, not all mice had pruritus after LL-37 injection (only 44%), which was consistent with mast cell activation. The relationship between LL-37 and mast cell activation remains to be further studied.
In addition, two neuropeptides related to pruritus were also found to be different between groups in this study. As an itch specific neurotransmitter and vasodilator, GRP may participate in flushing, telangiectasia, stinging and other relative sensations associated with pruritus of rosacea [
]. Natural polypeptide b (NPPB) is expressed on a subset of TRPV1 neurons, and is also coexpressed with neuropeptide Y Y2 receptor in neurons to participate in the itch induced by IL-31 [
]. Although NPPB is closely related to pruritus, it may not be involved in the conscious symptoms of rosacea. Because it and its related TRPV1, IL-31 was not increased in the pruritus group in this study. However, its increase in the non-pruritus group may require further verification of the sample size.
Previous work has shown that TRPV4 and TRPM8 can be activated by thermal stimuli [
], where TRPV4 is a heat-sensitive channel and TRPM8 is a cold-sensitive channel. In addition, these TRP channels are also have regulatory functions in itch and pain [
]. The enhanced expression levels of TRPV4 and TRPM8 in the skin and TG in pruritus mice suggest that temperature has a potential effect on pruritus through TRPV4 and TRPM8 channels. Furthermore, we observed high expression of TRPV4 and TRPM8 in keratinocytes by immunohistochemistry and fluorescence. Previous study has demonstrated that TRPV4 and TRPM8 can be expressed on various cells including nerve cells, keratinocytes, and immune cells [
]. Not only can TRP on nerve cells be involved in itch, but TRP on keratinocytes can also be directly involved. Activation of TRPV4 causes calcium influx into keratinocytes and upregulates the phosphorylation of mitogen-activated protein kinasein cells. TRPV4 keratinocyte-specific inducible knockout mice have significantly reduced acute histaminergic itch [
]. Meanwhile TRPM8 may be responsible for the stinging and burning sensations that accompany the cold pain, increasing the irritation caused by the cold [
]. We speculate that the increased expression of TRPM8 in skin and ganglia may be the cause of itching accompanied by stinging and burning in rosacea patients. Increased co-expression of TRPV4 and TRPM8 was associated with the appearance of these subjective symptoms and was also associated with the hot and cold biphasic temperature change.
The interaction between LL-37 and TRP channels on various cells has been previously reported. In rosacea, LL-37 induces inflammation by activating TRPV4 in mast cells, followed by cell degranulation [
]. Whether LL-37 can also induce activation of TRPV4 and TRPM8 channels on other immune cells or keratinocytes remains to be investigated.
In conclusion, on the basis of our clinical data, we confirmed that pruritus in patients with rosacea is often accompanied by complex subjective symptoms. And we suspected that the occurrence of pruritus was related to hot and cold temperatures. LL-37 can cause rosacea-like rash and scratching behavior in mice by multiple intradermal injections at low concentrations. Eventually, we revealed a potential effect of TRPV4 and TRPM8 on rosacea pruritus to some degree. TRPV4 may be responsible for thermal factors and itch, whereas TRPM8 may be responsible for cold stimulation and other complex sensations that accompany itching. However, we also need to distinguish this itch from other types of itch due to other pruritic skin diseases, psychological factors and so on. And the relationship between LL-37 and TRPV4, TRPM8 also needs to be further explored. After all, these efforts are still in their early stages due to the complexity of rosacea itching. We believe novel specific TRPV4 or TRPM8 modulatory chemicals are on the way to offer more options for rosacea patients to relieve their symptoms.
Funding
This work was supported by Scientific Research Project on Cadre Health Care in Sichuan Province (2020-229); and supported by Chengdu Technological Innovation Research and Development Project (2021-YF05-000579-SN); and supported by Clinical Research Innovation Project, West China Hospital, Sichuan University (19HXCX010); and supported by National Natural Science Foundation of China (82073473).
Evaluation of the effects of peptide antibiotics human beta-defensins-1/-2 and ll-37 on histamine release and prostaglandin d(2) production from mast cells.
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