Double deletion of tetraspanins CD9 and CD81 in mice leads to a syndrome resembling accelerated aging

Abstract

Chronic obstructive pulmonary disease (COPD) has been recently characterized as a disease of accelerated lung aging, but the mechanism remains unclear. Tetraspanins have emerged as key players in malignancy and inflammatory diseases. Here, we found that CD9/CD81 double knockout (DKO) mice with a COPD-like phenotype progressively developed a syndrome resembling human aging, including cataracts, hair loss, and atrophy of various organs, including thymus, muscle, and testis, resulting in shorter survival than wild-type (WT) mice. Consistent with this, DNA microarray analysis of DKO mouse lungs revealed differential expression of genes involved in cell death, inflammation, and the sirtuin-1 (SIRT1) pathway. Accordingly, expression of SIRT1 was reduced in DKO mouse lungs. Importantly, siRNA knockdown of CD9 and CD81 in lung epithelial cells additively decreased SIRT1 and Foxo3a expression, but reciprocally upregulated the expression of p21 and p53, leading to reduced cell proliferation and elevated apoptosis. Furthermore, deletion of these tetraspanins increased the expression of pro-inflammatory genes and IL-8. Hence, CD9 and CD81 might coordinately prevent senescence and inflammation, partly by maintaining SIRT1 expression. Altogether, CD9/CD81 DKO mice represent a novel model for both COPD and accelerated senescence.

Decreased salivary concentration of CD9 and CD81 exosome‐related tetraspanins may be associated with the periodontal clinical status

“…The foremost findings reported here were that the median levels of CD9 and CD81 exosomes are significantly decreased in the periodontitis patients in comparison with periodontally healthy controls, so that an altered exosome‐signalling pathway may constitute an important mechanism for periodontal pathogenesis. In agreement with the present findings, previous data have shown a potential pathogenic role for dysregulation of these proteins in both systemic inflammation (Suzuki et al., ; Takeda et al., , ; Wuttge et al., ) and delayed wound healing (Jiang et al., ; Zhang et al., ), suggesting a preventive role of tetraspanins CD9 and CD81 in senescence and inflammation (Jin et al., ; Takeda et al., ).…”

“…It has been stated that CD9 and CD81 are closely related tetraspanins that regulate inflammation not only through a spillover effect, but also by organization of multimolecular membrane complexes in tetraspanin‐enriched microdomains (Jin et al., ; Takeda et al., ). However, the precise underlying mechanisms for this regulation are not fully elucidated.…”

“…However, the precise underlying mechanisms for this regulation are not fully elucidated. While some authors hypothesize that CD9 and CD81‐enriched microdomains negatively regulate lipopolysaccharide (LPS)‐induced receptor activation by stabilizing CD14/Toll‐like receptor 4 (TLR4) complexes (Jin et al., ; Suzuki et al., ), other observations suggest that the co‐deficiency of CD9 and CD81 function seems to be sufficient for macrophages to increase matrix metalloproteinase (MMP)‐2 and MMP‐9 production as well as to suppress cell motility (Takeda et al., , ). In the present study, not only the correlation between salivary concentration of CD9 and CD81 exosomes regarding clinical parameters such as PD, CAL and extent was negatively significant, but also a significant downward trend concerning the stage and grade of disease could be identified.…”

“…Taking into account not only that salivary tetraspanins are reliable exosomal biomarkers for diagnostic and prognostic assessments (Andreu & Yáñez‐Mó, ; Lau & Wong, ), but also that compelling evidence suggests multiple roles of tetraspanins in immune cell recruitment and migration (Yeung, Hickey, & Wright, ), as well as a preventive role in systemic inflammation (Jin et al., ; Takeda, Suzuki, Jin, & Tachibana, ; Takeda et al., ), this study aimed to evaluate whether the association of the salivary concentration of CD9 and CD81 exosome‐related tetraspanins with the periodontal clinical status may be useful to determine the risk of developing periodontal disease.…”

Cholesterol sensing by CD81 is important for hepatitis C virus entry

“…CD81 performs this role via partnership with CD19; first by chaperoning CD19 through the secretory pathway and then by dictating its cell surface distribution, which permits proper assembly of the B-cell receptor complex upon activation [9][10][11][12]. Through other molecular partnerships CD81 has been implicated in additional physiological processes such as T-cell receptor signalling, cell migration, growth factor signalling, sperm-egg fusion and most recently, biological ageing [13][14][15][16][17][18].…”