My lab's CAP inspection is finally over!!! Now I can get back to more regular blogging (without guilt).
This month's American Journal of Pathology features an intriguing article that proposes a central role for receptor for advanced glycation end products (RAGE) in the pathogenesis of asthma (abstract).
First, some background. RAGE is a multiligand receptor for ligands including S100 proteins, HMGB1, amyloid beta, and heparin. There are two forms of RAGE: membrane RAGE (mRAGE) which is thought to be proinflammatory, and soluble (i.e., cytoplasmic) RAGE (sRAGE) considered to be anti-inflammatory. RAGE transcripts and proteins are preferentially expressed in lung.
This study uses a house dust mite (HDM) antigen sensitization/challenge model in RAGE knockout (RAGE-ko) mice to directly assess the role of RAGE in asthma/allergic airway disease (A3D). The authors confirm these results using a different model, ovalbumin, to confirm that the same effects of RAGE are independent of the antigen challenge.
The authors measured cell counts in BALF obtained from Diff-Quik stained sections; they measured BALF for levels of eotaxin, eotaxin-2, IL-4, IL-5, and IL-13 by ELISA. The prepared RNA from whole lung and performed qRT-PCR for RAGE, IL-5, and IL-13. FFPE lung was examined for RAGE by immunofluorescence and tissue eosinophilia. Finally (if you can picture this), they measured respiratory mechanics in both wt and RAGE-ko mice.
Most of the measures of A3D are not seen in RAGE-knockout mice after HDM challenge compared to wt mice. Following HDM challenge, RAGE-knockout mice showed no significant changes in pulmonary function testing; no increased eosinophilic infiltrates, goblet cell hyperplasia, or increased mucin expression; no increases in IL-5, IL-13, eotaxin, or eotaxin-2. The latter suggests that canonical mediators of eosinophil recruitment and airway remodeling are abrogated in the absence of RAGE and that RAGE likely acts as a proximal mediator in one or more proinflammatory pathways that lead to the functional and pathologic changes seen in A3D. However, IL-4, IgE, and HDM-specific IgG1 are the same between wt and RAGE-knockout mice--indicating that humoral immunity remains intact in the absence of RAGE and that IgE alone does not appear to play a significant role in this model. The ovalbumin model showed similar data indicating that the role of RAGE in murine A3D is independent of the particular epitopes involved in antigen sensitization and challenge.
This is a very interesting paper that challenges some longstanding ideas about the understanding of the pathogenesis of asthma. Certainly worth noting as follow-up studies come out.