In Jun Yeo

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‐1β, 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.

Upregulation of genes and coexpression networks related to immune function and inflammation have been repeatedly reported in the brain of individuals with schizophrenia. However, a causal relationship between the abnormal immune/inflammation-related gene expression and schizophrenia has not been determined. We conducted co-expression networks using publicly available RNA-seq data from prefrontal cortex (PFC) and hippocampus (HP) of 64 individuals with schizophrenia and 64 unaffected controls from the SMRI tissue collections. We identified proinflammatory cytokine, transmembrane tumor necrosis factor-α (tmTNFα), as a potential regulator in the module of co-expressed genes that we find related to the immune/inflammation response in endothelial cells (ECs) and/or microglia of the brain of individuals with schizophrenia. The immune/inflammation-related modules associated with schizophrenia and the TNF signaling pathway that regulate the network were replicated in an independent cohort of brain samples from 68 individuals with schizophrenia and 135 unaffected controls. To investigate the association between the overexpression of tmTNFα in brain ECs and schizophrenia-like behaviors, we induced short-term overexpression of the uncleavable form of (uc)-tmTNFα in ECs of mouse brain for 7 weeks. We found schizophrenia-relevant behavioral deficits in these mice, including cognitive impairment, abnormal sensorimotor gating, and sensitization to methamphetamine (METH) induced locomotor activity and METH-induced neurotransmitter levels. These uc-tmTNFα effects were mediated by TNF receptor2 (TNFR2) and induced activation of TNFR2 signaling in astrocytes and neurons. A neuronal module including neurotransmitter signaling pathways was down-regulated in the brain of mice by the short-term overexpression of the gene, while an immune/inflammation-related module was up-regulated in the brain of mice after long-term expression of 22 weeks. Our results indicate that tmTNFα may play a direct role in regulating neurotransmitter signaling pathways that contribute to the clinical features of schizophrenia.

Alzheimer’s disease (AD) is closely related to neuroinflammation, and the increase in inflammatory cytokine generation and inducible nitric oxide synthase (iNOS) expression in the brain of a patient with AD is well known. Excessive cytokines can stimulate iNOS in microglia and astroglia and overproduce nitric oxide, which can be toxic to neurons. The disease–gene–drug network analysis based on the GWAS/OMIM/DEG records showed that miconazole (MCZ) affected AD through interactions with NOS. Inhibiting iNOS can reduce neuroinflammation, thus preventing AD progression. To investigate the prophylactic role of antifungal agent in the AD development, a lipopolysaccharide-induced memory disorder mouse model was used, and cognitive function was assessed by Morris water maze test and passive avoidance test. MCZ treatment significantly attenuated cognitive impairment, suppressed iNOS and cyclooxygenase-2 expression, and activation of astrocyte and microglial BV2 cells, as well as reduced cytokine levels in the brains and lipopolysaccharide-treated astrocytes and microglia BV2 cells. In further mechanism studies, Pull-down assay and iNOS luciferase activity data showed that MCZ binds to iNOS and inhibited transcriptional activity. Our results suggest that MCZ is useful for ameliorating the neuroinflammation-mediated AD progression by blocking iNOS expression.

Park JH, et al. Allergy Asthma Immunol Res. 2019 Jul;11(4):548-559. https://doi.org/10.4168/aair.2019.11.4.548