ABSTRACT
[This corrects the article e22 in vol. 21, PMID: 34277112.].
ABSTRACT
BACKGROUND AND PURPOSE: Chitinase-3-like 1 (CHI3L1) causes skin inflammation in the progression of atopic dermatitis. We investigated if anti-CHI3L1 antibody could prevent the development of atopic dermatitis and its mechanisms of action. EXPERIMENTAL APPROACH: The effect of CHI3L1 antibody on phthalic anhydride-induced atopic dermatitis animal model and in vitro reconstructed human skin (RHS) model were investigated. Expression and release of atopic dermatitis-related cytokines were determined using an enzyme-linked immunosorbent assay, and RT-qPCR, STAT3 and CXCL8 signalling were measured by western blotting. KEY RESULTS: Anti-CHI3L1 antibody suppressed phthalic anhydride-induced epidermal thickening, clinical score, IgE level and infiltration of inflammatory cells, and reduced phthalic anhydride-induced inflammatory cytokines concentration. In addition, CHI3L1 antibody treatment inhibited the expression of STAT3 activity in phthalic anhydride-treated skin. It was also confirmed that CHI3L1 antibody treatment alleviated atopic dermatitis-related inflammation in the RHS model. The inhibitory effects of CHI3L1 antibody was similar or more effective compared with that of the IL-4 antibody. We further found that CHI3L1 is associated with CXCL8 by protein-association network analysis. siRNA of CHI3L1 blocked the mRNA levels of CHI3L1, IL-1ß, IL-4, CXCL8, TSLP, and the expression of CHI3L1 and p-STAT, and the level of CXCL8, whereas recombinant level of CXCL8 was elevated. Moreover, siRNA of STAT3 reduced the mRNA level of these cytokines. CHI3L1 and p-STAT3 expression correlated with the reduced CXCL8 level in the RHS in vitro model. CONCLUSION AND IMPLICATIONS: Our data demonstrated that CHI3L1 antibody could be a promising effective therapeutic drug for atopic dermatitis.
Subject(s)
Chitinase-3-Like Protein 1 , Dermatitis, Atopic , Interleukin-8 , STAT3 Transcription Factor , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/immunology , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , Humans , Animals , Interleukin-8/metabolism , Chitinase-3-Like Protein 1/antagonists & inhibitors , Chitinase-3-Like Protein 1/metabolism , Skin/drug effects , Skin/pathology , Skin/metabolism , Male , Mice, Inbred BALB C , Phthalic Anhydrides/pharmacology , Antibodies/pharmacology , Mice , Female , Inflammation/drug therapy , Inflammation/metabolismABSTRACT
The relationship between schizophrenia (SCZ) and cancer development remains controversial. Based on the disease-gene association platform, it has been revealed that tumor necrosis factor receptor (TNFR) could be an important mediatory factor in both cancer and SCZ development. TNF-α also increases the expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) in the development of SCZ and tumor, but the role of TNFR in mediating the association between the two diseases remains unclear. We studied the vital roles of TNFR2 in the progression of tumor and SCZ-like behavior using A549 lung cancer cell xenografted TNFR2 knockout mice. TNFR2 knockout mice showed significantly decreased tumor size and weight as well as schizophrenia-like behaviors compared to wild-type mice. Consistent with the reduced tumor growth and SCZ-like behaviors, the levels of TrkB and BDNF expression were significantly decreased in the lung tumor tissues and pre-frontal cortex of TNFR2 knockout mice. However, intravenous injection of BDNF (160 µg/kg) to TNFR2 knockout mice for 4 weeks increased tumor growth and SCZ-like behaviors as well as TrkB expression. In in vitro study, significantly decreased cell growth and expression of TrkB and BDNF by siTNFR2 transfection were found in A549 lung cancer cells. However, the addition of BDNF (100 ng/ml) into TNFR2 siRNA transfected A549 lung cancer cells recovered cell growth and the expression of TrkB. These results suggest that TNFR2 could be an important factor in mediating the comorbidity between lung tumor growth and SCZ development through increased TrkB-dependent BDNF levels.
Subject(s)
Brain-Derived Neurotrophic Factor , Lung Neoplasms , Mice, Knockout , Receptor, trkB , Receptors, Tumor Necrosis Factor, Type II , Schizophrenia , Animals , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/genetics , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Lung Neoplasms/genetics , Humans , Mice , Schizophrenia/metabolism , Schizophrenia/genetics , Receptors, Tumor Necrosis Factor, Type II/metabolism , Receptors, Tumor Necrosis Factor, Type II/genetics , Receptors, Tumor Necrosis Factor, Type II/deficiency , Receptor, trkB/metabolism , Receptor, trkB/genetics , A549 Cells , Male , Behavior, Animal/drug effects , Cell Proliferation/drug effects , Mice, Inbred C57BL , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolismABSTRACT
Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly upregulated by various inflammatory and immunological diseases, including several cancers, Alzheimer's disease, and atherosclerosis. Several studies have shown that CHI3L1 can be considered as a marker of disease diagnosis, prognosis, disease activity, and severity. In addition, the proinflammatory action of CHI3L1 may be mediated via responses to various proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1ß, interleukin-6, and interferon-γ. Therefore, CHI3L1 may contribute to a vast array of inflammatory diseases. However, its pathophysiological and pharmacological roles in the development of inflammatory diseases remain unclear. In this article, we review recent findings regarding the roles of CHI3L1 in the development of inflammatory diseases and suggest therapeutic approaches that target CHI3L1.