Chemokine responses distinguish chemical-induced allergic from irritant skin inflammation: Memory T cells make the difference

Background

As clinical and histological features of allergic and irritant contact dermatitis share common characteristics, the differentiation between them in the preclinical and clinical evaluations of chemicals remains difficult.

Objective

To identify the differences in the underlying immunological mechanisms of chemical-induced allergic or irritant skin responses.

Methods

We systematically studied the involvement of chemokines in both diseases by quantitative real-time polymerase chain reaction in mice and humans. The cellular origin of relevant chemokines and receptors was determined using immunohistochemistry; functional relevance was demonstrated in vitro by transwell chemotaxis and in vivo by adoptive transfer experiments using a model of hapten-induced murine contact hypersensitivity.

Results

Independent of overall skin inflammation, chemical-induced allergic and irritant skin responses showed distinct molecular expression profiles. In particular, chemokine genes predominantly regulated by T-cell effector cytokines demonstrated differential upregulation in hapten-specific skin inflammation. Notably, the expression of CXCR3 ligands, such as CXCL9 (Mig) and CXCL10 (IP-10), was upregulated in chemical-induced allergic skin responses when compared with irritant skin responses. Furthermore, we showed that inflammatory chemokines such as CXCL10 prime leukocytes to respond to CXCL12 (SDF-1), increasing their recruitment both in vitro and in vivo.

Conclusion

We provide important insights into the molecular basis of chemical-induced allergic and irritant contact dermatitis, identify novel markers suitable for their differentiation, and demonstrate the cooperation of inflammatory and homeostatic chemokines in the recruitment of pathogenic leukocyte subsets.

Clinical implications

Molecular differences between both diseases represent the basis for new approaches to diagnostics and therapy.

Key words: Allergy, chemokines, chemotaxis, inflammation, cell trafficking, irritancy, memory T cells, skin, T_H1/T_H2 cells

Abbreviations used: DC, Dendritic cell, DNFB, Dinitrofluorobenzene, DNP, Dinitrophenyl, MCP, Monocyte chemotactic protein, MIP, Macrophage inflammatory protein, NiSO₄, Nickel sulphate, SLS, Sodium lauryl sulfate