Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation.

Levin, M.C., Jirholt, P., Wramstedt, A., Johansson, M.E., Lundberg, A.M., Gustafsson, T.M., Ståhlman, M., Fogelstrand, P., Brisslert, M., Fogelstrand, L., Yan, Z.Q., Hansson, G.K., Björkback, H., Olofsson, S.O., Borén, J.

Journal	Circ Res.	Year	2011
Species	Mouse	Volume	109 (11)
Analytes Measured	IFN-γ, IL-10, IL-12 total, IL-6, MCP-1, TNF-α	Page #	1210-1218
Matrix Tested	Cell culture supernatants, Plasma	Category	Cytokines & Chemokines

Abstract

RATIONALE: The innate immune system and in particular the pattern-recognition receptors Toll-like receptors have recently been linked to atherosclerosis. Consequently, inhibition of various signaling molecules downstream of the Toll-like receptors has been tested as a strategy to prevent progression of atherosclerosis. Receptor-interacting protein 2 (Rip2) is a serine/threonine kinase that is involved in multiple nuclear factor-κB (NFκB) activation pathways, including Toll-like receptors, and is therefore an interesting potential target for pharmaceutical intervention.

OBJECTIVE: We hypothesized that inhibition of Rip2 would protect against development of atherosclerosis.

METHODS AND RESULTS: Surprisingly, and contrary to our hypothesis, we found that mice transplanted with Rip2(-/-) bone marrow displayed markedly increased atherosclerotic lesions despite impaired local and systemic inflammation. Moreover, lipid uptake was increased whereas immune signaling was reduced in Rip2(-/-) macrophages. Further analysis in Rip2(-/-) macrophages showed that the lipid accumulation was scavenger-receptor independent and mediated by Toll-like receptor 4 (TLR4)-dependent lipid uptake.

CONCLUSIONS: Our data show that lipid accumulation and inflammation are dissociated in the vessel wall in mice with Rip2(-/-) macrophages. These results for the first time identify Rip2 as a key regulator of cellular lipid metabolism and cardiovascular disease.