Possible roles of long-chain sphingomyelines and sphingomyelin synthase 2 in mouse macrophage inflammatory response

Sakamoto, Hitomi; Yoshida, Tetsuya; Sanaki, Takao; Shigaki, Shuhei; Morita, Hirotoshi; Oyama, Miki; Mitsui, Masaru; Tanaka, Yoshikazu; Nakano, Toru; Mitsutake, Susumu; Igarashi, Yasuyuki; Takemoto, Hiroshi

doi:10.1016/j.bbrc.2016.11.041

Cited by 34 publications

(24 citation statements)

References 29 publications

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“…[ 20 ] SMS2 knockout significantly decreased very long chain SM species [SM(d18:1/22:0) and SM(d18:1/24:0)] in plasma, although long chain SM species did not change. [ 21 ] Interestingly, addition of SM(d18:1/24:0) or SM(d18:1/16:0) strongly induced the expression of ICAM‐1 and iNOS in macrophages, suggesting a role of SM in the modulation of macrophage activation and inflammation. Consistent with these results, we found that five SM species positively associated with low AMY1 copy numbers were also positively associated with inflammatory markers.…”

Section: Discussionmentioning

confidence: 99%

Low AMY1 Copy Number Is Cross‐Sectionally Associated to an Inflammation‐Related Lipidomics Signature in Overweight and Obese Individuals

Mayneris‐Perxachs

Mousa

Naderpoor

et al. 2020

Molecular Nutrition Food Res

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Scope Reduced amylase 1 (AMY1) copy numbers are associated with obesity, insulin resistance, and inflammation. Although mechanisms linking AMY1 copy number with metabolic disorders are poorly understood, recent findings suggest that lipids play a key role. Methods and results Plasma lipidomic signatures associated with AMY1 copy number are explored in 57 non‐diabetic overweight/obese subjects aged 18–60. Serum amylase and inflammatory cytokines levels are also measured. AMY1 copy number is strongly associated with the serum amylase concentration. Participants are divided into low‐(≤4) and high‐(>4) AMY1 carriers based on the median. Low‐AMY1 carriers have higher BMI and fat mass. They also have higher levels of dihexosylceramides (R = −0.27, p = 0.044), cholesterol esters (CE) (R = −0.32, p = 0.020), alkylphosphatidylcholines [PC(O)] (R = −0.33, p = 0.014), and sphingomyelins (SM) (R = −0.38, p = 0.005). From 459 lipid species, 28 differ between low‐ and high‐AMY1 carriers. These include CE species with long‐chain PUFA; PC(O) and PC plasmalogens containing arachidonic acid; and PC, mono‐, di‐, and tri‐hexosylceramides, and SM containing saturated fatty acids (mainly C16:0 and C20:0). This lipidomic signature is strongly associated with inflammatory cytokines, which are also negatively associated with the AMY1 copy number. Conclusion A lipidomics signature associated with low AMY1 copy numbers is revealed, which is linked to obesity and chronic low‐grade inflammation.

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Section: Discussionmentioning

confidence: 99%

Low AMY1 Copy Number Is Cross‐Sectionally Associated to an Inflammation‐Related Lipidomics Signature in Overweight and Obese Individuals

Mayneris‐Perxachs

Mousa

Naderpoor

et al. 2020

Molecular Nutrition Food Res

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“…Moreover, Sakamoto et al showed that a large amount of exogenous SM (50-100 μM) increased ICAM-1 transcription in peritoneal macrophages, suggesting the importance of the SM/ceramide balance to regulate ICAM-1 through transmembrane signaling. 43 Some reports have suggested the possibility that other sphingolipids and their metabolisms affected by SMS2 deficiency are involved in the reduction of ICAM-1 expression. Clarke et al showed that TNF-α induced activation and translocation of neutral sphingomyelinase-2 (nSMase2) to the plasma membrane through p38 MAPK in the enhancement of ICAM-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Deficiency of sphingomyelin synthase 2 prolongs survival by the inhibition of lymphoma infiltration through ICAM‐1 reduction

et al. 2020

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The tumor microenvironment (TME) formation involving host cells and cancer cells through cell adhesion molecules (CAMs) is essential for the multiple steps of cancer metastasis and growth. Sphingomyelin synthase 2 (SMS2) is involved in inflammatory diseases such as obesity and diabetes mellitus by regulation of the SM/ceramide balance. However, the involvement of SMS2 in TME formation and metastasis is largely unknown. Here, we report that SMS2‐deficient (SMS2‐KO) mice show suppressed the EL4 cell infiltration to liver and prolonged survival time. ICAM‐1 was identified as a candidate for the inhibition of TME formation in immortalized mouse embryonic fibroblasts (tMEFs) from mRNA array analysis for CAMs. Reduced SM/ceramide balance in SMS2‐KO tMEFs suppressed the attachment of EL4 cells through transcriptional reduction of ICAM‐1 by the inhibition of NF‐κB activation. TNF‐α‐induced NF‐κB activation and subsequent induction of ICAM‐1 were suppressed in SMS2‐KO tMEFs but restored by SMS2 re‐introduction. In the EL4 cell infiltration mouse model, EL4 injection increased ICAM‐1 expression in WT liver but not in SMS2‐KO mouse liver. Therefore, inhibition of SMS2 may be a therapeutic target to suppress the infiltration of malignant lymphoma.

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“…Further, we see an elevation in ceramide (d18:1/24:1), previously shown to have roles in arteriosclerosis, obesity, diabetes, and inflammation. In addition, long-chain sphingomyelins, derived from ceramides, activate macrophages inducing an inflammatory response [ 93 ]. These shifts in ceramides have been shown to have a role in astrocyte cell death and mediated cognitive impairment [ 94 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet

et al. 2018

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Recent work suggests that diet affects brain metabolism thereby impacting cognitive function. Our objective was to determine if a western diet altered brain metabolism, increased blood-brain barrier (BBB) transport and inflammation, and induced cognitive impairment in C57BL/6 (WT) mice and low-density lipoprotein receptor null (LDLr -/-) mice, a model of hyperlipidemia and cognitive decline. We show that a western diet and LDLr -/- moderately influence cognitive processes as assessed by Y-maze and radial arm water maze. Also, western diet significantly increased BBB transport, as well as microvessel factor VIII in LDLr -/- and microglia IBA1 staining in WT, both indicators of activation and neuroinflammation. Interestingly, LDLr -/- mice had a significant increase in 18F- fluorodeoxyglucose uptake irrespective of diet and brain 1H-magnetic resonance spectroscopy showed increased lactate and lipid moieties. Metabolic assessments of whole mouse brain by GC/MS and LC/MS/MS showed that a western diet altered brain TCA cycle and β-oxidation intermediates, levels of amino acids, and complex lipid levels and elevated proinflammatory lipid mediators. Our study reveals that the western diet has multiple impacts on brain metabolism, physiology, and altered cognitive function that likely manifest via multiple cellular pathways.

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Possible roles of long-chain sphingomyelines and sphingomyelin synthase 2 in mouse macrophage inflammatory response

Cited by 34 publications

References 29 publications

Low AMY1 Copy Number Is Cross‐Sectionally Associated to an Inflammation‐Related Lipidomics Signature in Overweight and Obese Individuals

Low AMY1 Copy Number Is Cross‐Sectionally Associated to an Inflammation‐Related Lipidomics Signature in Overweight and Obese Individuals

Deficiency of sphingomyelin synthase 2 prolongs survival by the inhibition of lymphoma infiltration through ICAM‐1 reduction

Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet

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