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Background: We previously showed that mice lacking MΦLRP1-/- (low-density lipoprotein receptor-related protein 1 in macrophages) undergo accelerated atherosclerotic plaque formation due to changes in macrophages including increased apoptosis, decreased efferocytosis, and exaggerated transition to the inflammatory M1 phenotype. Here we sought to explore the role of macrophage low-density lipoprotein receptor-related protein 1 during regression of atherosclerosis since regressing plaques are characterized by transitioning of macrophages to M2 status as inflammation resolves.Methods: Apolipoprotein E-/- mice on a high-fat diet for 12 weeks were reconstituted with bone marrow from apolipoprotein E-producing wild-type or MΦLRP1-/- mice, and then placed on a chow diet for 10 weeks (n=9 to 11 mice/group). A cohort of apolipoprotein E-/- mice reconstituted with apolipoprotein E-/- bone marrow served as baseline controls (n=9).Results: Plaques of both wild-type and MΦLRP1-/- bone marrow recipients regressed compared with controls (11% and 22%, respectively; P<0.05), and plaques of MΦLRP1-/- recipients were 13% smaller than those of wild-type recipients ( P<0.05). Recipients of MΦLRP1-/- marrow had 36% fewer M1 macrophages ( P<0.01) and 2.5-fold more CCR7 (C-C chemokine receptor type 7)-positive macrophages in the plaque relative to wild-type mice ( P<0.01). Additionally, in vivo studies of cellular egress showed a 4.6-fold increase in 5-ethynyl-2´-deoxyuridine-labeled CCR7+ macrophages in mediastinal lymph nodes. Finally, in vivo studies of reverse cholesterol transport showed a 1.4-fold higher reverse cholesterol transport in MΦLRP1-/- recipient mice ( P<0.01).Conclusions: Absence of macrophage low-density lipoprotein receptor-related protein 1 unexpectedly accelerates atherosclerosis regression, enhances reverse cholesterol transport, and increases expression of the motility receptor CCR7, which drives macrophage egress from lesions. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate whether exogenous hydrogen sulfide (H2S) can protect the RAW264.7 macrophages against the inflammation induced by free fatty acids (FFA) by blunting NLRP3 inflammasome activation via a specific TLR4/NF-κB pathway. Methods: RAW264.7 macrophages were exposed to increasing concentrations of FFA for up to 3 days to induce FFA-induced inflammation. The cells were pretreated with NaHS (a donor of H2S) before exposure to FFA. Cell viability, cell apoptosis, TLR4, NF-κB, NLRP3 inflammasome, IL- 1β, IL-18 and cleaved caspase-3 expression were measured by a combination of MTT assay, ELISA, and immunoblotting. Results: H2S attenuated FFA-induced cell apoptosis, and reduced the expression of NLRP3, ASC, pro-caspase-1, caspase-1, IL- 1β, IL-18 and caspase-3. In addition, H2S inhibited the FFA-induced activation of TLR4 and NF-κB. Furthermore, NLRP3 inflammasome activation was regulated by the TLR4 and NF-κB pathway. Conclusion: The present study demonstrated for the first time that H2S appears to suppress FFA-induced macrophage inflammation and apoptosis by inhibiting the TLR4/ NF-κB pathway and its downstream NLRP3 inflammasome activation. Thus H2S might possess potential in the treatment of diseases resulting from FFA overload like insulin resistance and type diabetes. [ABSTRACT FROM AUTHOR]