The inflammatory cytokine response of cholesterol-enriched macrophages is dampened by stimulated pinocytosis

• Published in: Journal of leukocyte biology Vol. 81; no. 2; pp. 483 - 491
• Main Authors: Li, Yankun, Tabas, Ira
• Format: Journal Article
• Language: English
• Published: United States Society for Leukocyte Biology 01.02.2007
• Subjects: Animals; atherosclerosis; Cells, Cultured; Cholesterol - pharmacology; Down-Regulation - drug effects; Inflammation; Lysosomes - drug effects; Lysosomes - immunology; Macrophage Colony-Stimulating Factor - immunology; Macrophages - drug effects; Macrophages - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; M‐CSF; Pinocytosis - drug effects; Pinocytosis - immunology; Structure-Activity Relationship; TNF; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - immunology; Tumor Necrosis Factor-alpha - secretion
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.0806518

Two features of advanced atherosclerotic lesions are large numbers of macrophages and a heightened state of inflammation. Some of the macrophages appear to be enriched with free cholesterol (FCMφs), and we have shown that this process induces the synthesis and secretion of inflammatory cytokines, including TNF‐α and IL‐6. However, lesions contain many other macrophages that are not FC‐enriched (non‐FCMφs). Therefore, we sought to understand how the interaction of these two populations of macrophages would influence the inflammatory response. We show here that non‐FCMφs possess a robust ability to deplete TNF‐α and IL‐6 secreted by FCMφs. The mechanism involves enhanced pinocytic uptake and lysosomal degradation of the FCMφ‐secreted cytokines by the non‐FCMφs. The FCMφs contribute directly to this process by secreting pinocytosis‐stimulatory factors that act on non‐FCMφs but not on the FCMφs themselves. One of these pinocytosis‐stimulatory factors is M‐CSF, which is induced by a process involving cholesterol trafficking to the endoplasmic reticulum and signaling through PI‐3K and ERK MAPK pathways. However, one or more other FCMφ‐secreted factors are also required for stimulating pinocytosis in non‐FCMφs. Thus, FCMφs secrete inflammatory cytokines as well as factors that promote the eventual pinocytosis and degradation of these cytokines by neighboring macrophages. This process may normally serve to prevent prolonged or disseminated effects of inflammatory cytokines during inflammation. Moreover, possible perturbation of stimulated pinocytosis during the progression of advanced atherosclerosis may contribute to the heightened inflammatory state of these lesions.