Le récepteur CD40 est exprimé dans l’adipocyte chez l’homme: implication dans le dialogue inflammatoire entre lymphocytes et adipocytes

Abstract

Aims/hypothesis

Obesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor super-family member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation.

Methods

CD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohisto-chemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralizing antibodies in lymphocyte/adipocyte coculture.

Results

CD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal-vascular fraction. CD40 expression was up regulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein-kinase (MAPK) activation, stimulated inflammatory adipocytokin production, and decreased insulin-induced glucose transport in parallel with a down regulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte-adipocyte coculture led to an up regulation of proinflammatory adipocytokins and a down regulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell-cell contact. Blocking the CD40/CD40L interaction with neutralizing antibodies reduced IL-6 secretion from adipocytes.

Conclusions/interpretation

Adipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokin production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.