ALCAM (CD166) contributes to inflammation in the footpad model of delayed type hypersensitivity

Introduction: RAGE is a multiligand binding receptor known to play a role in late diabetic complications. However, RAGE-/– mice are only partly protected from late diabetic complications, while blockade of ligand/AGE interaction by sRAGE mediates a nearly complete protection. This implies the presence of other receptors involved in pathophysiological settings, in which RAGE-ligands are likely to contribute to the outcome. Experimental models of the adaptive immune response have identified ALCAM (CD166) as a likely candidate to bind one or more of the RAGE ligands.

Aims: We studied the effects of ALCAM blockade using wildtype (WT) and RAGE-/– mice in the delayed type hypersensitivity (DTH) model of adaptive immunity in the absence or presence of sALCAM and ALCAM neutralizing antibodies in order to define the role of ALCAM as RAGE-substituting receptor.

Methods: 8 weeks old male WT and RAGE-/– mice were sensitized by injection of 100µl 25mg/ml mBSA, 50mg/ml Dextran, 50% Freunds incomplete adjuvant over the left inguinal lymph node. 21 days later DTH reaction was induced (footpad injection 50µl 0,25mg/ml mBSA/ Control – Ovalbumin). sRAGE, sALCAM and ALCAM antibody were applied i.p. (100µg/mouse) 6h before and 6 and 12h after mBSA. 24h after footpad injection mice were sacrificed and the footpads examined morphologically for signs of swelling and inflammation and clinical score obtained.

Results: Administration of sRAGE led to significant decrease of inflammation in the footpads of both WT and RAGE-/–mice. sALCAM and ALCAM neutralizing antibodies, however, significantly reduced inflammation only in RAGE-/– but not in WT mice.

Conclusion: ALCAM is a RAGE homologue receptor that modulates inflammatory responses upon RAGE-ligand activation in vivo.