Selective impairment of TLR2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis
Habib Hasannejad Department of Dermatology, Kyorin University School of Medicine, Tokyo, Japan
Abstract:
Background: The skin of atopic dermatitis (AD) exhibits a striking susceptibility to infection with Gram-positive bacteria and herpes simplex virus (HSV) which are known to stimulate Toll-like receptor (TLR) 2.
Objective: We asked whether TLR2-mediated proinflammatory cytokine production by monocytes is selectively impaired in patients with AD, and, if so, whether high FcRI levels on the monocytes could be related to the impairment.
Methods: The two subpopulations of monocytes, CD14dim proinflammatory and CD14bright classical monocytes, from patients with AD and normal healthy controls were stimulated to produce IL-1 and TNF- with PMA/ionomycin, LPS (TLR4 ligand) or Pam3Cys (TLR2 ligand) for 4h and stimultaneous flow-cytometric assessment of surface phenotype and intracellular cytokine synthesis was performed. Surface expression of TLR2, TLR4, and FcRI on the monocyte subpopulations was also assessed by flow cytometry.
Results: TLR2-mediated IL-1 and TNF- production by either the CD14dim or the CD14bright monocytes was found to be selectively impaired in patients with AD. The most remarkable reduction in TLR2-mediated proinflammatory cytokine production was observed in CD14dim monocytes expressing high FcRI levels from AD patients, but not in those expressing low FcRI levels: while the corresponding FcRIhigh populations were able to respond normally to LPS stimulation of TNF- production.
Conclusion: Monocytes, particularly the proinflammatory monocytes, from AD patients are functionally defective in their capacity to produce proinflammatory cytokines upon TLR2 stimuli due to high levels of their FcRI expression.
Clinical implications: This selective impairment of monocytes would explain why AD patients are specifically susceptible to cutaneous staphylococcal and streptococcal and HSV infections.
