All‑trans retinoic acid promotes macrophage phagocytosis and decreases inflammation via inhibiting CD14/TLR4 in acute lung injury

Li,Shuangxue; Lei,Yuansheng; Lei,Jieyun; Li,Hui

doi:10.3892/mmr.2021.12508

All‑trans retinoic acid promotes macrophage phagocytosis and decreases inflammation via inhibiting CD14/TLR4 in acute lung injury

Authors:
- Shuangxue Li
- Yuansheng Lei
- Jieyun Lei
- Hui Li
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Affiliations: Department of Respiratory and Critical Care Medicine, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China, Department of Neurology, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, P.R. China, Department of Cardiology, Taiyuan Central Hospital, Taiyuan, Shanxi 030009, P.R. China, Department of Gynecology, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030012, P.R. China
Published online on: October 21, 2021 https://doi.org/10.3892/mmr.2021.12508
Article Number: 868
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Acute lung injury (ALI) is a common clinical emergency and all‑trans retinoic acid (ATRA) can alleviate organ injury. Therefore, the present study investigated the role of ATRA in ALI. Lipopolysaccharide (LPS)‑induced ALI rats were treated with ATRA and the arterial partial pressure of oxygen (PaO₂), lung wet/dry weight (W/D) ratio and protein content in the bronchial alveolar lavage fluid (BALF) were measured to evaluate the effect of ATRA on ALI rats. Alveolar macrophages were isolated from the BALF. The phagocytic function of macrophages was detected using the chicken erythrocyte phagocytosis method and flow cytometry. The viability of macrophages was measured using a Cell Counting Kit‑8 assay, and apoptosis was analyzed using a TUNEL assay and flow cytometry. The expression levels of Toll‑like receptor 4 (TLR4) and cluster of differentiation (CD)14 on the macrophage membrane were detected by immunofluorescence staining. The protein levels of TLR4, CD14, phosphorylated (p)‑65, p65, p‑IκBα and IκBα were analyzed using western blotting. The concentrations of IL‑6, IL‑1β and macrophage inflammatory protein‑2 in the plasma of rats were detected by ELISA. Macrophages were treated with IAXO‑102 (TLR4 inhibitor) to verify the involvement of CD14/TLR4 in the effect of ATRA on ALI. ATRA provided protection against LPS‑induced ALI, as evidenced by the increased PaO2 and reduced lung W/D ratio and protein content in the BALF. ATRA enhanced macrophage phagocytosis and viability and reduced apoptosis and inflammation in ALI rats. Mechanically, ATRA inhibited CD14 and TLR4 expression and NF‑κB pathway activation. ATRA enhanced macrophage phagocytosis and reduced inflammation by inhibiting the CD14/TLR4‑NF‑κB pathway in LPS‑induced ALI. In summary, ATRA inactivated the NF‑κB pathway by inhibiting the expression of CD14/TLR4 receptor in the alveolar macrophages of rats, thus enhancing the phagocytic function of macrophages in ALI rats, improving the activity of macrophages, inhibiting apoptosis, reducing the levels of inflammatory factors, and consequently playing a protective role in ALI model rats. This study may offer novel insights for the clinical management of ALI.

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1	Elicker BM, Jones KT, Naeger DM and Frank JA: Imaging of acute lung injury. Radiol Clin North Am. 54:1119–1132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Fröhlich S, Boylan J and McLoughlin P: Hypoxia-induced inflammation in the lung: A potential therapeutic target in acute lung injury? Am J Respir Cell Mol Biol. 48:271–279. 2013. View Article : Google Scholar : PubMed/NCBI
3	Gouda MM and Bhandary YP: Acute lung injury: IL-17A-mediated inflammatory pathway and its regulation by curcumin. Inflammation. 42:1160–1169. 2019. View Article : Google Scholar : PubMed/NCBI
4	Mokra D, Mikolka P, Kosutova P and Mokry J: Corticosteroids in acute lung injury: The dilemma continues. Int J Mol Sci. 20:47652019. View Article : Google Scholar : PubMed/NCBI
5	Perl M, Lomas-Neira J, Venet F, Chung CS and Ayala A: Pathogenesis of indirect (secondary) acute lung injury. Expert Rev Respir Med. 5:115–126. 2011. View Article : Google Scholar : PubMed/NCBI
6	Barbalho SM, de Goulart RA and Batista G: Vitamin A and inflammatory bowel diseases: From cellular studies and animal models to human disease. Expert Rev Gastroenterol Hepatol. 13:25–35. 2019. View Article : Google Scholar : PubMed/NCBI
7	Chen F, Cao Y, Qian J, Shao F, Niederreither K and Cardoso WV: A retinoic acid-dependent network in the foregut controls formation of the mouse lung primordium. J Clin Invest. 120:2040–2048. 2010. View Article : Google Scholar : PubMed/NCBI
8	Nagpal I and Wei LN: All-trans retinoic acid as a versatile cytosolic signal modulator mediated by CRABP1. Int J Mol Sci. 20:36102019. View Article : Google Scholar : PubMed/NCBI
9	Sierra-Mondragon E, Rodriguez-Munoz R, Namorado-Tonix C, Molina-Jijon E, Romero-Trejo D, Pedraza-Chaverri J and Reyes JL: All-trans retinoic acid attenuates fibrotic processes by downregulating TGF-β1/Smad3 in early diabetic nephropathy. Biomolecules. 92:5252019. View Article : Google Scholar : PubMed/NCBI
10	Yu D, Cai SY, Mennone A, Vig P and Boyer JL: Cenicriviroc, a cytokine receptor antagonist, potentiates all-trans retinoic acid in reducing liver injury in cholestatic rodents. Liver Int. 38:1128–1138. 2018. View Article : Google Scholar : PubMed/NCBI
11	Uniyal S, Dhasmana A, Tyagi A and Muyal JP: ATRA reduces inflammation and improves alveolar epithelium regeneration in emphysematous rat lung. Biomed Pharmacother. 108:1435–1450. 2018. View Article : Google Scholar : PubMed/NCBI
12	Kawasaki T, Ito K, Miyata H, Akira S and Kawai T: Deletion of PIKfyve alters alveolar macrophage populations and exacerbates allergic inflammation in mice. EMBO J. 36:1707–1718. 2017. View Article : Google Scholar : PubMed/NCBI
13	Huang P, Wei S, Huang W, Wu P, Chen S, Tao A, Wang H, Liang Z, Chen R, Yan J and Zhang Q: Hydrogen gas inhalation enhances alveolar macrophage phagocytosis in an ovalbumin-induced asthma model. Int Immunopharmacol. 74:1056462019. View Article : Google Scholar : PubMed/NCBI
14	Moser EK, Field NS and Oliver PM: Aberrant Th2 inflammation drives dysfunction of alveolar macrophages and susceptibility to bacterial pneumonia. Cell Mol Immunol. 15:480–492. 2018. View Article : Google Scholar : PubMed/NCBI
15	Bonhomme D, Santecchia I, Vernel-Pauillac F, Caroff M, Germon P, Murray G, Adler B, Boneca IV and Werts C: Leptospiral LPS escapes mouse TLR4 internalization and TRIFassociated antimicrobial responses through O antigen and associated lipoproteins. PLoS Pathog. 16:e10086392020. View Article : Google Scholar : PubMed/NCBI
16	Wu X, Kong Q, Zhan L, Qiu Z, Huang Q and Song X: TIPE2 ameliorates lipopolysaccharide-induced apoptosis and inflammation in acute lung injury. Inflamm Res. 68:981–992. 2019. View Article : Google Scholar : PubMed/NCBI
17	Intengan HD and Smyth DD: Renal alpha 2a/d-adrenoceptor subtype function: Wistar as compared to spontaneously hypertensive rats. Br J Pharmacol. 121:861–866. 1997. View Article : Google Scholar : PubMed/NCBI
18	Sun A, Wang W, Ye X, Wang Y, Yang X, Ye Z, Sun X and Zhang C: Protective effects of methane-rich saline on rats with lipopolysaccharide-induced acute lung injury. Oxid Med Cell Longev. 2017:74301932017. View Article : Google Scholar : PubMed/NCBI
19	Xia H, Ge Y, Wang F, Ming Y, Wu Z, Wang J, Sun S, Huang S, Chen M, Xiao W and Yao S: Protectin DX ameliorates inflammation in sepsis-induced acute lung injury through mediating PPARγ/NF-κB pathway. Immunol Res. 68:280–288. 2020. View Article : Google Scholar : PubMed/NCBI
20	Li Q, Ran Q, Sun L, Yin J, Luo T, Liu L, Zhao Z, Yang Q, Li Y, Chen Y, et al: Lian Hua Qing Wen Capsules, a potent epithelial protector in acute lung injury model, block proapoptotic communication between macrophages, and alveolar epithelial cells. Front Pharmacol. 11:5227292020. View Article : Google Scholar : PubMed/NCBI
21	Yi R, Wei Y, Tan F, Mu J, Long X, Pan Y, Liu W and Zhao X: Antioxidant capacity-related preventive effects of shoumei (Slightly Fermented Camellia sinensis) polyphenols against hepatic injury. Oxid Med Cell Longev. 2020:93293562020. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Li B, Gao MH, Lv CY, Yang P and Yin QF: Study of the synergistic effects of all-transretinoic acid and C-phycocyanin on the growth and apoptosis of A549 cells. Eur J Cancer Prev. 25:97–101. 2016. View Article : Google Scholar : PubMed/NCBI
24	Miao J, Ye S, Lan J, Ye P, Wen Q, Mei L, Liu X, Lin J, Zhou X, Du S, et al: Nuclear HMGB1 promotes the phagocytic ability of macrophages. Exp Cell Res. 393:1120372020. View Article : Google Scholar : PubMed/NCBI
25	Wang C, Petriello MC, Zhu B and Hennig B: PCB 126 induces monocyte/macrophage polarization and inflammation through AhR and NF-κB pathways. Toxicol Appl Pharmacol. 367:71–81. 2019. View Article : Google Scholar : PubMed/NCBI
26	Leláková V, Beraud-Dufour S, Hošek J, Šmejkal K, Prachyawarakorn V, Pailee P, Widmann C, Václavík J, Coppola T, Mazella J, et al: Therapeutic potential of prenylated stilbenoid macasiamenene F through its anti-inflammatory and cytoprotective effects on LPS-challenged monocytes and microglia. J Ethnopharmacol. 263:1131472020. View Article : Google Scholar : PubMed/NCBI
27	Liu TY, Zhao LL, Chen SB, Hou BC, Huang J, Hong X, Qing L, Fang Y and Tao Z: Polygonatum sibiricum polysaccharides prevent LPS-induced acute lung injury by inhibiting inflammation via the TLR4/Myd88/NF-κB pathway. Exp Ther Med. 20:3733–3739. 2020.PubMed/NCBI
28	Zhang Y, Zhu Y, Gao G and Zhou Z: Knockdown XIST alleviates LPS-induced WI-38 cell apoptosis and inflammation injury via targeting miR-370-3p/TLR4 in acute pneumonia. Cell Biochem Funct. 37:348–358. 2019. View Article : Google Scholar : PubMed/NCBI
29	Mohning MP, Thomas SM, Barthel L, Mould KJ, McCubbrey AL, Frasch SC, Bratton DL, Henson PM and Janssen WJ: Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK. Am J Physiol Lung Cell Mol Physiol. 314:L69–L82. 2018. View Article : Google Scholar : PubMed/NCBI
30	Liu ZM, Wang KP, Ma J and Zheng SG: The role of all-trans retinoic acid in the biology of Foxp3+ regulatory T cells. Cell Mol Immunol. 12:553–557. 2015. View Article : Google Scholar : PubMed/NCBI
31	Zhou TB, Ou C, Jiang ZP, Xiong MR and Zhang F: Potential signal pathway between all-trans retinoic acid and LMX1B in hypoxia-induced renal tubular epithelial cell injury. J Recept Signal Transduct Res. 36:53–56. 2016. View Article : Google Scholar : PubMed/NCBI
32	Amengual J, Ribot J, Bonet ML and Palou A: Retinoic acid treatment increases lipid oxidation capacity in skeletal muscle of mice. Obesity (Silver Spring). 16:585–591. 2008. View Article : Google Scholar : PubMed/NCBI
33	Elshal M, Abu-Elsaad N, El-Karef A and Ibrahim T: Retinoic acid modulates IL-4, IL-10 and MCP-1 pathways in immune mediated hepatitis and interrupts CD4+ T cells infiltration. Int Immunopharmacol. 75:1058082019. View Article : Google Scholar : PubMed/NCBI
34	Wu J, Wan X, Zhang H, Li W, Ma M, Pan B, Liang X and Cao C: Retinoic acid attenuates contrast-induced acute kidney injury in a miniature pig model. Biochem Biophys Res Commun. 512:163–169. 2019. View Article : Google Scholar : PubMed/NCBI
35	Leem AY, Shin MH, Douglas IS, Song JH, Chung KS, Kim EY, Jung JY, Kang YA, Chang J, Kim YS and Park MS: All-trans retinoic acid attenuates bleomycin-induced pulmonary fibrosis via downregulating EphA2-EphrinA1 signaling. Biochem Biophys Res Commun. 491:721–726. 2017. View Article : Google Scholar : PubMed/NCBI
36	Zhang Y, Zhao J, Sun J, Huang L and Li Q: Targeting lung cancer initiating cells by all-trans retinoic acid-loaded lipid-PLGA nanoparticles with CD133 aptamers. Exp Ther Med. 16:4639–4649. 2018.PubMed/NCBI
37	Mokra D and Kosutova P: Biomarkers in acute lung injury. Respir Physiol Neurobiol. 209:52–58. 2015. View Article : Google Scholar : PubMed/NCBI
38	Liu W, Liu K, Zhang S, Shan L and Tang J: Tetramethylpyrazine showed therapeutic effects on sepsis-induced acute lung injury in rats by inhibiting endoplasmic reticulum stress protein kinase RNA-Like endoplasmic reticulum kinase (PERK) signaling-induced apoptosis of pulmonary microvascular endothelial cells. Med Sci Monit. 24:1225–1231. 2018. View Article : Google Scholar : PubMed/NCBI
39	Zhou H, Li F, Niu JY, Zhong WY, Tang MY, Lin D, Cui HH, Huang XH, Chen YY, Wang HY and Tu YS: Ferroptosis was involved in the oleic acid-induced acute lung injury in mice. Sheng Li Xue Bao. 71:689–697. 2019.PubMed/NCBI
40	Yang C, Yang X, Du J, Wang H, Li H, Zeng L, Gu W and Jiang J: Retinoic acid promotes the endogenous repair of lung stem/progenitor cells in combined with simvastatin after acute lung injury: A stereological analysis. Respir Res. 16:1402015. View Article : Google Scholar : PubMed/NCBI
41	Jeddi R, Mansouri R, Kacem K, Gouider E, Abid HB, Belhadjali Z and Meddeb B: Transfusion-related acute lung injury (TRALI) during remission induction course of acute myeloid leukemia: A possible role for all-transretinoic-acid (ATRA)? Pathol Biol (Paris). 57:500–502. 2009. View Article : Google Scholar : PubMed/NCBI
42	Uniyal S, Tyagi AK and Muyal JP: All trans retinoic acid (ATRA) progresses alveolar epithelium regeneration by involving diverse signalling pathways in emphysematous rat. Biomed Pharmacother. 131:1107252020. View Article : Google Scholar : PubMed/NCBI
43	Seifart C, Muyal JP, Plagens A, Yildirim AÖ, Kohse K, Grau V, Sandu S, Reinke C, Tschernig T, Vogelmeier C and Fehrenbach H: All-trans retinoic acid results in irregular repair of septa and fails to inhibit proinflammatory macrophages. Eur Respir J. 38:425–439. 2011. View Article : Google Scholar : PubMed/NCBI
44	Ramirez-Moreno A, Escorza MA, Garza RG, Hady K, Valenzuela AM, Marszalek JE, Sharara-Núñez I and Delgadillo-Guzmán D: All-trans retinoic acid improves pancreatic cell proliferation on induced type 1 diabetic rats. Fundam Clin Pharmacol. 34:345–351. 2020. View Article : Google Scholar : PubMed/NCBI
45	Chen X, Tang J, Shuai W, Meng J, Feng J and Han Z: Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome. Inflamm Res. 69:883–895. 2020. View Article : Google Scholar : PubMed/NCBI
46	Lo HM, Wang SW, Chen CL, Wu PH and Wu WB: Effects of all-trans retinoic acid, retinol, and beta-carotene on murine macrophage activity. Food Funct. 5:140–148. 2014. View Article : Google Scholar : PubMed/NCBI
47	Zhang Z, Zhang Y and Zhou R: Loss of annexin A5 expression attenuates the lipopolysaccharide-induced inflammatory response of rat alveolar macrophages. Cell Biol Int. 44:391–401. 2020. View Article : Google Scholar : PubMed/NCBI
48	Huang X, Xiu H, Zhang S and Zhang G: The role of macrophages in the pathogenesis of ALI/ARDS. Mediators Inflamm. 2018:12649132018. View Article : Google Scholar : PubMed/NCBI
49	James ML, Ross AC, Nicola T, Steele C and Ambalavanan N: VARA attenuates hyperoxia-induced impaired alveolar development and lung function in newborn mice. Am J Physiol Lung Cell Mol Physiol. 304:L803–L812. 2013. View Article : Google Scholar : PubMed/NCBI
50	Jeyaseelan S, Chu HW, Young SK, Freeman MW and Worthen GS: Distinct roles of pattern recognition receptors CD14 and toll-like receptor 4 in acute lung injury. Infect Immun. 73:1754–1763. 2005. View Article : Google Scholar : PubMed/NCBI
51	Chen Z, Ding X, Jin S, Pitt B, Zhang L, Billiar T and Li Q: WISP1-αvβ3 integrin signaling positively regulates TLR-triggered inflammation response in sepsis induced lung injury. Sci Rep. 6:288412016. View Article : Google Scholar : PubMed/NCBI
52	Ren W, Wang Z, Hua F and Zhu L: Plasminogen activator inhibitor-1 regulates LPS-induced TLR4/MD-2 pathway activation and inflammation in alveolar macrophages. Inflammation. 38:384–393. 2015. View Article : Google Scholar : PubMed/NCBI
53	Ma L, Wu XY, Zhang LH, Chen WM, Uchiyama A, Mashimo T and Fujino Y: Propofol exerts anti-inflammatory effects in rats with lipopolysaccharide-induced acute lung injury by inhibition of CD14 and TLR4 expression. Braz J Med Biol Res. 46:299–305. 2013. View Article : Google Scholar : PubMed/NCBI
54	Sierra-Mondragon E, Molina-Jijon E, Namorado-Tonix C, Rodriguez-Munoz R, Pedraza-Chaverri J and Reyes JL: All-trans retinoic acid ameliorates inflammatory response mediated by TLR4/NF-κB during initiation of diabetic nephropathy. J Nutr Biochem. 60:47–60. 2018. View Article : Google Scholar : PubMed/NCBI
55	Tang SE, Wu SY, Chu SJ, Tzeng YS, Peng CK, Lan CC, Perng WC, Wu CP and Huang KL: Pre-treatment with ten-minute carbon dioxide inhalation prevents lipopolysaccharide-induced lung injury in mice via down-regulation of toll-like receptor 4 expression. Int J Mol Sci. 20:62932019. View Article : Google Scholar : PubMed/NCBI
56	Gu B, Miao J, Fa Y, Lu J and Zou S: Retinoic acid attenuates lipopolysaccharide-induced inflammatory responses by suppressing TLR4/NF-kappaB expression in rat mammary tissue. Int Immunopharmacol. 10:799–805. 2010. View Article : Google Scholar : PubMed/NCBI