The Mechanism Of Toll Like Receptor 2 Mediate Chronic Itch

Objective:Pruritus is a sensation that causes intense discomfort in people.It often occurs in various chronic skin diseases.The typical symptom of psoriasis and xeroderma is pruritus,which seriously affects the quality of life of patients.As a kind of pattern recognition receptor,toll-like receptors(TLRs)often play a role in immune diseases.Now,the existing data suggests that TLRs are also involved in the pruritus.Therefore,this paper focuses on TLR2,psoriasis,xeroderma and explores the relationship between TLR2 and chronic itch.Firstly,the changes of TLR2 m RNA and protein were detected in mouse models of psoriasis and xeroderma.Then the molecular mechanism of chronic itch controlled by TLR2 signaling pathway was explored through pharmacology,behavior and molecular biology.Methods:1 CQ,48/80,Substance P,and ET-1 were injected into the nape of the neck of wild-type mice and TLR2 KO mice to observe the scratching behavior and detect the changes of acute itch.2 The wild-type mice and TLR2 KO mice were respectively divided into two groups,one group was not treated,the other group was established chronic itch model;Mouse scratching behavior was observed at specific time points during the modeling process.After 7 days of modeling,the pathological changes of the skin were detected by H&E staining.The TLR2 m RNA and protein expression were detected by fluorescence Q-PCR and Western blotting.The m RNA of chemokines CXCL1,CXCL2,CXCL3,CXCL5,CXCL7,CXCL8,and chemokine receptors CXCR1 and CXCR2 were detected by the Q-PCR.3 The wild-type mice and TLR2 KO mice were divided into two groups,one group was not treated,the other group was established chronic itch model.After 7 days of modeling,CXCR1 and CXCR2 inhibitors were injected intradermally into the nape of the neck of the mice in both groups to observe the scratching behavior of the mice and detect changes in pruritus.4 Wild-type mice were randomly divided into groups.Mice were given intradermal injections of CQ,CQ + CXCR1/2 inhibitor mixture,and 48/80,48/80 + CXCR1/2 inhibitors mixture,respectively.6-10 mice in each group were observed for scratching behavior and the changes of acute itch.5 The change of p65 and p38 phosphorylation was detected by Western blotting in Ha Ca T cell with PGN-SA treatment.6 Treatment of p65 and p38 inhibitors in Ha Ca T cell line followed by incubation of Ha Ca T cell line with PGN-SA,and the expression of chemokine CXCL1 and CXCL8 were determined by Q-PCR.7 The neck back of the mice was injected intradermally with CXCL8 to observe the scratching behavior and detect the acute itch induced by CXCL8.8 Wild-type mice were treated with imiquimod to establish a chronic itch mouse model.And then,they were randomly divided into three groups.In the neck,normal saline,0.1 ?g CXCL8,and 0.3 ?g CXCL8 were intradermally injected respectively to observe scratching behavior.It was examined whether CXCL8 can increase the itch of a chronic itchy mouse model.Results:1 The number of scratching was reduced in TLR2 KO mice.2 The expression of TLR2 m RNA and protein increased in the skin of chronic itch model,and the m RNA expression of CXCR1 and CXCR2 in DRG was up-regulated.In the chronic itch model of TLR2 KO mice,itch reduced;the skin thickness was thinned,and the upregulation of CXCL1 and CXCL8 m RNA in the skin was reduced.3 Intradermal injections of inhibitors of CXCR1 and CXCR2 reduced spontaneous itch in psoriasis and xeroderma models.4 Intradermal injections of inhibitors of CXCR1 and CXCR2 can reduce the number of scratches induced by itch agent.5 After PGN-SA incubated Ha Ca T cell lines,the expression of P-p65 and P-p38 proteins,CXCL1 and CXCL8 m RNA were up-regulated.6 Inhibition of p65 phosphorylation can remit the up-regulation of CXCL1 and CXCL8 m RNA expression induced by PGN-SA.7 CXCL8 can induce acute itch.8 Low-dose recombinant proteins CXCL8 increase the spontaneous pruritus in psoriasis and xeroderma models.Conclusions:1 TLR2 participates in acute itch and chronic itch.2 TLR2 regulates the expression of CXCL1 and CXCL8 through NF-?B signaling pathway.3 TLR2 mediate chronic itch by regulating CXCL1 and CXCL8.