IRAK regulates macrophage foam cell formation by modulating genes involved in cholesterol uptake and efflux.
Interleukin-1 receptor-associated kinase-1 (IRAK1) is linked to the pathogenesis of atherosclerosis; however, its role in macrophage foam cell formation is not known. Therefore, the present study investigated the role of IRAK1 in lipid uptake, biosynthesis, and efflux in THP-1 derived macrophages and human monocyte-derived macrophages (HMDMs). Ox-LDL (40 μg/mL, 15 minutes-48 hours) treatment induced time-dependent increase in IRAK1, IRAK4, and Stat1 activation in THP-1 derived macrophages. IRAK1/4 inhibitor (INH) or IRAK1 siRNA significantly attenuated cholesterol accumulation, DiI-Ox-LDL binding, and uptake while cholesterol efflux to apoAI and HDL was enhanced in THP-1 derived macrophages and HMDMs. Ox-LDL treatment significantly increased the mRNA expression of CD36, LOX-1, SR-A, ABCA1, ABCG1, Caveolin-1, CYP27A1 while that of SR-BI was decreased. IRAK1/4 inhibition or IRAK1 knockdown, however, attenuated Ox-LDL-induced CD36 expression; augmented ABCA1 and ABCG1 expression while expression of others was unaffected in THP-1 derived macrophages and HMDMs. Moreover, IRAK1/4 inhibition had no significant effect on genes involved in lipid biosynthesis. In IRAK1/4 INH pre-treated THP-1 derived macrophages Ox-LDL-induced Stat1 phosphorylation and its binding to CD36 promoter was significantly attenuated while LXRα expression and its binding to the ABCA1/ABCG1 locus, NFATc2 activation and its binding to ABCA1 locus was enhanced. The present study thus demonstrates that IRAK regulates lipid accumulation by modulating CD36-mediated uptake and ABCA1-, ABCG1-dependent cholesterol efflux. Therefore, IRAK1 can be a potential target for preventing macrophage foam cell formation.
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Minakshi
M
Rana
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Amit
A
Kumar
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Rajiv Lochan
RL
Tiwari
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Vishal
V
Singh
Department of Transfusion Medicine, King George's Medical University, Lucknow, Uttar Pradesh, India.
Tulika
T
Chandra
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Madhu
M
Dikshit
Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, India.
Manoj Kumar
MK
Barthwal
D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018955:CD36 Antigens; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D002784:Cholesterol; C507768:IRAK1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
CD36; foam cell; interleukin-1 receptor-associated kinase; lipid uptake; liver X receptor α; nuclear factor of activated T cell; signal transducer and activator of transcription 1