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.
Antonopoulos
C
C
Center for Dermatology, Department of Medicine, University College London, London, United Kingdom.
Cumberbatch
M
M
Dearman
R J
RJ
Daniel
R J
RJ
Kimber
I
I
Groves
R W
RW
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