Clusterin Modulates Allergic Airway Inflammation by Attenuating CCL20-Mediated Dendritic Cell Recruitment

Abstract

Recruitment and activation of dendritic cells (DCs) in the lungs are critical for Th2 responses in asthma, and CCL20 secreted from bronchial epithelial cells (BECs) is known to influence the recruitment of DCs. Because asthma is a disease that is closely associated with oxidative stress, we hypothesized that clusterin, an oxidative stress regulatory molecule, may have a role in the development of allergic airway inflammation. The aim of this study was to examine whether clusterin regulates CCL20 production from the BECs and the subsequent DC recruitment in the lungs. To verify the idea, clusterin knockout (Clu−/−), clusterin heterogeneous (Clu+/−), and wild-type mice were exposed intranasally to house dust mite (HDM) extract to induce allergic airway inflammation. We found that the total number of immune cells in bronchoalveolar lavage fluid and the lung was increased in Clu−/− and Clu+/− mice. Of these immune cells, inflammatory DCs (CD11b+CD11c+) and Ly6Chigh monocyte populations in the lung were significantly increased, which was accompanied by increased levels of various chemokines, including CCL20 in bronchoalveolar lavage fluid, and increased oxidative stress markers in the lung. Moreover, HDM-stimulated human BECs with either up- or downregulated clusterin expression showed that CCL20 secretion was negatively associated with clusterin expression. Interestingly, clusterin also reduced the level of intracellular reactive oxygen species, which is related to induction of CCL20 expression after HDM stimulation. Thus, the antioxidant property of clusterin is suggested to regulate the expression of CCL20 in BECs and the subsequent recruitment of inflammatory DCs in the airway.

Olfactory dysfunction in the pathophysiological continuum of dementia

“…The study suffers from the referral bias from the sampled population and the lack of phenotype classification but provides an additional piece of evidence that chronic inflammation in response to infection may underlie the development of PD (Bower et al, 2006). Taken the emergent role of ApoE (Zhang et al, 2011;Gonzalez et al, 2017), clusterin (CLU) (Falgarone and Chiocchia, 2009;Hong et al, 2016), triggering receptor expressed on myeloid cells 2 (TREM2) in innate immunity (Fahrenhold et al, 2018;Jay et al, 2015;Shi and Holtzman, 2018), and their convergence as risk variants for sporadic AD, it is likely that an altered inflammatory response to exogenous substances in the airways is transferred through the olfactory neuroepithelium to the connected olfactory circuitry. This is supported by the increased infections incidence of viruses in ApoEε4 carriers (HSV-1, HIV1, Hepatitis C, Hepatitis B) (Itzhaki et al, 1997;Burgos et al, 2006;Finch and Morgan, 2007;Burt et al, 2008;Hishiki et al, 2010;Yin et al, 2010) and bacteria (C. Pneumoniae, Gram negative bacteria) (de Bont et al, 1999;Van Oosten et al, 2001;Kattan et al, 2008).…”

Rediscovery of NF‐κB signaling in nasopharyngeal carcinoma: How genetic defects of NF‐κB pathway interplay with EBV in driving oncogenesis?

“…Treg cells are consistently detected in NPC biopsies (Lau et al, ; Yip, Abdullah, Yusoff, & Seow, ). In addition to recruitment of DCs (Hong et al, ), CCL20/CCR6 axis mediates the migration of in CD4(+) FOXP3(+) regulatory T cells (Tregs) into inflammatory tissues (Cook et al, ; Zhang, Kang, & Zhao, ). Expression of CCL20 is positively correlated with Treg markers (FoxP3 and IL‐10) in multiple human cancers (Frick et al, ; Liu et al, ; Zhang, Qi, et al, ).…”

“…CCL20 belongs to the CC chemokine subfamily and is ligand for CCR6 (Lee, Phan, Hulett, & Korner, 2015) and is a direct target gene of NF-κB (Ignacio, Kabir, Lee, Adunyah, & Son, 2016). CCL20 is known to influence the recruitment of DCs (Hong et al, 2016).…”

Role of epithelial chemokines in the pathogenesis of airway inflammation in asthma (Review)

“…It has also been indicated that CCL11 and CCL20 are produced following IL-4 or IL-13 stimulation (25). Furthermore, it has been demonstrated that clusterin induces the production of CCL20 by regulating the oxidative stress environment in airway epithelial cells from mice studies (26). Previous studies have demonstrated that microRNA-34a, 15-lipoxygenase and histamine are important regulators for CCL22 in airway epithelial cells (27)(28)(29).…”

“…C-C chemokine receptor CCR6, IL-33R and TSLPR (corresponding receptors for CCL20, IL-33 and TSLP respectively) are expressed on immature DCs (iDCs). By binding with these receptors, CCL20, IL-33 and TSLP activate iDCs and promote their maturation (26,42). DCs then migrate to the T cell zone in mediastinal lymph nodes, where they activate T cells via antigen presentation and co-stimulation.…”