TY - JOUR
T1 - IRAK regulates macrophage foam cell formation by modulating genes involved in cholesterol uptake and efflux
AU - Rana, Minakshi
AU - Kumar, Amit
AU - Tiwari, Rajiv Lochan
AU - Singh, Vishal
AU - Chandra, Tulika
AU - Dikshit, Madhu
AU - Barthwal, Manoj Kumar
N1 - Funding Information:
The financial support to MKB from DBT and CSIR network Project Thunder is acknowledged. We gratefully acknowledge the Indian Council of Medical Research (ICMR), New Delhi, India for the award of research fellowships to M. Rana; University Grant Commission (UGC), New Delhi, India to A. Kumar; Council of Scientific and Industrial Research (CSIR), New Delhi, India to R. L. Tiwari and V. Singh. The excellent technical help of Mr. A.L. Vishwakarma and Mrs. M. Chaturvedi for the Flow Cytometry study from Sophisticated Analytical Instrument Facility; CSIR-CDRI, Lucknow is also acknowledged. Technical assistance by Mr. C. P. Pandey from Central Instrument Facility; Pharmacology Division; CSIR-CDRI, Lucknow is also acknowledged. This manuscript is CSIR-CDRI communication no. 9215.
Publisher Copyright:
© 2016 WILEY Periodicals, Inc.
PY - 2016/7/1
Y1 - 2016/7/1
N2 - 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.
AB - 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.
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U2 - 10.1002/bies.201600085
DO - 10.1002/bies.201600085
M3 - Article
C2 - 27270491
AN - SCOPUS:84976592575
SN - 0265-9247
VL - 38
SP - 591
EP - 604
JO - BioEssays
JF - BioEssays
IS - 7
ER -