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

• Published in: Journal of allergy and clinical immunology 2007-07, Vol.120 (1), p.69-75
• Main Authors: Hasannejad, Habib, MD, PhD, Takahashi, Ryo, PhD, Kimishima, Momoko, BS, Hayakawa, Kazuhito, MD, PhD, Shiohara, Tetsuo, MD, PhD
• Format: Article
• Language: English
• Subjects: Adult; Allergy and Immunology; Alzheimer's disease; atopic dermatitis; Biological and medical sciences; Cytokines; Cytokines - biosynthesis; Dementia; Dermatitis, Atopic - immunology; FcɛRI; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immune system; Infections; Inflammation Mediators - metabolism; Lipopolysaccharide Receptors - analysis; Male; Medical sciences; Middle Aged; Monocytes - classification; Monocytes - immunology; Older people; Proinflammatory monocytes; Receptors, IgE - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Toll-like receptor 2; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - metabolism
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2007.04.010

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 FcεRI levels on the monocytes could be related to the impairment. Methods The 2 subpopulations of monocytes, CD14dim proinflammatory and CD14bright classical monocytes, from patients with AD and healthy control subjects were stimulated to produce IL-1β and TNF-α 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 FcεRI on the monocyte subpopulations was also assessed by means of flow cytometry. Results TLR2-mediated IL-1β and TNF-α production by either the CD14dim or 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 FcεRI levels from patients with AD. This reduction was restored by means of downregulation of their FcεRI 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 FcεRI 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.