Selective impairment of Toll-like receptor 2-mediated proinflammatory cytokine production by monocytes from patients with atopic dermatitis

Background: The skin of patients with 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 investigated whether TLR2-mediated proinflammatory cytokine production by monocytes is selectively impaired in patients with AD and, if so, whether high Fc epsilon.RI levels on the monocytes could be related to the impairment. Methods: The 2 subpopulations of monocytes, CD14(dim) proinflammatory and CD14(bright) classical monocytes, from patients with AD and healthy control subjects were stimulated to produce IL-1 beta and TNF-a with phorbol 12-myristate 13-acetate/ionomycin, LPS (TLR4 ligand), or Pam3Cys (TLR2 ligand) for 4 hours, and simultaneous flow cytometric assessment of surface phenotype and intracellular cytokine synthesis was performed. Surface expression of TLR2, TLR4, and Fc epsilon RI on the monocyte subpopulations was also assessed by means of How cytometry. Results: TLR2-mediated IL-1 beta and TNF-a production by either the CD14(dim), or CD14(bright) monocytes was found to be selectively impaired in patients with AD. The most remarkable reduction in TLR2-mediated proinflammatory cytokine production was observed in CD14(dim) monocytes expressing high Fc epsilon RI levels from patients with AD. This reduction was restored by means of downregulation of their Fc epsilon RI expression after preculture in the absence of IgE. Conclusion: Monocytes, particularly the proinflammatory monocytes, from patients with AD are functionally defective in their capacity to produce proinflammatory cytokines on TLR2 stimuli in part because of the high levels of their Fc epsilon RI expression. Clinical implications: This selective impairment of monocytes would explain why patients with AD are specifically susceptible to cutaneous staphylococcal and streptococcal and HSV infections.