Functional caspase-1 is required for Langerhans cell migration and optimal contact sensitization in mice.
Langerhans cell (LC) migration from epidermis to draining lymph node is a critical first step in cutaneous immune responses. Both TNF-alpha and IL-1 beta are important signals governing this process, but the potential regulatory role of IL-1 alpha processing by caspase-1 is unknown. In wild-type (WT) mice, application of the contact allergens 2,4-dinitrofluorobenzine and oxazolone lead to a marked reduction in epidermal LC numbers, but in caspase-1-deficient mice this reduction was not observed. Moreover, although intradermal injection of TNF-alpha (50 ng) induced epidermal LC migration in WT mice, this cytokine failed to induce LC migration in caspase-1-deficient mice. Intradermal IL-1 beta (50 ng) caused a similar reduction in epidermal LC numbers in both WT and caspase-1-deficient mice, indicating that, given an appropriate signal, caspase-1-deficient epidermal LC are capable of migration. Contact hypersensitivity to both 2,4-dinitrofluorobenzine and oxazolone was inhibited in caspase-1-deficient mice, indicating a functional consequence of the LC migration defect. In organ culture the caspase-1 inhibitor Ac-YVAD-cmk, but not control peptide, potently inhibited the epidermal LC migration that occurs in this system, and reduced spontaneous migration of LC was observed in skin derived from caspase-1-deficient mice. Moreover, Ac-YVAD-cmk applied to BALB/c mouse skin before application of contact sensitizers inhibited LC migration and contact hypersensitivity in vivo. Taken together, these data indicate that caspase-1 may play a central role in the regulation of LC migration and suggest that the activity of this enzyme is amenable to control by specific inhibitors both in vivo and in vitro.
Center for Dermatology, Department of Medicine, University College London, London, United Kingdom.
C
C
Antonopoulos
M
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Cumberbatch
R J
RJ
Dearman
R J
RJ
Daniel
I
I
Kimber
R W
RW
Groves
D000279:Administration, Cutaneous; D000590:Amino Acid Chloromethyl Ketones / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D061945:Caspase Inhibitors; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003877:Dermatitis, Contact / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D004139:Dinitrofluorobenzene / Q000008:administration & dosage; D005260:Female; D006241:Haptens / Q000008:administration & dosage; D007165:Immunosuppression Therapy; D007271:Injections, Intradermal; D007375:Interleukin-1 / Q000008:administration & dosage; D007801:Langerhans Cells / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D006241:Haptens; D007375:Interleukin-1; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D014409:Tumor Necrosis Factor-alpha; D004139:Dinitrofluorobenzene; D020170:Caspase 1