Immunity as Cornerstone of Non-alcoholic Fatty Liver Disease: The Contribution of Innate and Adaptive Immune Mechanisms in the Pathogenesis of the Metabolic Syndrome-related Steatohepatitis
,
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major hepatic manifestation of metabolic syndrome and encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). This study aimed to evaluate the contribution of immunological, inflammatory, and metabolic parameters-including cytokine levels, immune cell profiles, and microRNA (miR) expression-in the progression from NAFLD to NASH among individuals with features of metabolic syndrome.
An observational study was conducted between January 2022 and December 2024, enrolling 300 adult patients with radiologically or histologically confirmed NAFLD. Patients underwent comprehensive anthropometric, biochemical, and immunological assessments, including cytokine profiling (interleukin [IL]-6, IL-17, tumor necrosis factor-α [TNF-α], transforming growth factor-β1 [TGF-β1]), immune cell phenotyping (T helper 17 [TH17], regulatory T cells [Tregs], monocytes), and miR quantification (miR-122, miR-34a). Liver biopsy was performed in 95 selected cases.. The nursing team also assists in coordinating multidisciplinary care and ensuring follow-up compliance, which are vital for long-term disease management and reducing progression to NASH.
Significant elevations were observed in metabolic parameters (body mass index [BMI], homeostatic model assessment for insulin resistance [HOMA-IR]), hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST]), inflammatory markers (high-sensitivity C-reactive protein [hs-CRP], ferritin), and oxidative stress markers (malondialdehyde [MDA]). Adipokines (↑leptin, ↓adiponectin), hepatokines (↑fibroblast growth factor 21 [FGF21], ↑fetuin-A), and cytokines (↑IL-6, ↑TNF-α, ↑IL-17) were markedly altered in patients with biopsy-proven NASH.
This study reinforces that pro-inflammatory cytokines, altered immune cell profiles, and dysregulated miRs serve as promising biomarkers for early identification and potential therapeutic targeting in metabolic syndrome-associated steatohepatitis.
1. Indenmeyer CC, McCullough AJ. The natural history of nonalcoholic fatty liver disease—An evolving view. Clin Liver Dis. 2018;22(1):11–21.
2. Abenavoli L, Boccuto L, Federico A, Dallio M, Loguercio C, Di Renzo L, et al. Diet and non-alcoholic fatty liver disease: The Mediterranean way. Int J Environ Res Public Health. 2019;16(17):3011.
3. Wijarnpreecha K, Aby ES, Ahmed A, Kim D. Evaluation and management of extrahepatic manifestations of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2020;26(2):168–78.
4. Samuel VT, Shulman GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 2018;27(1):22–41.
5. Tanase DM, Gosav EM, Petrov D, Jucan AE, Lacatusu CM, Floria M, et al. Involvement of ceramides in non-alcoholic fatty liver disease (NAFLD) atherosclerosis (ATS) development: Mechanisms and therapeutic targets. Diagnostics (Basel). 2021;11(11):2053.
6. Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, et al. Non-alcoholic fatty liver disease (NAFLD): A review of pathophysiology, clinical management, and effects of weight loss. BMC Endocr Disord. 2022;22:63.
7. Ali A, Amin MJ, Ahmed MU, Taj A, Aasim M, Tabrez E. Frequency of non-alcoholic fatty liver disease (NAFLD) and its associated risk factors among Type-2 diabetics. Pak J Med Sci. 2022;38(1):28–33.
8. Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011;6(8):e23937.
9. Pedersen JS, Rygg MO, Serizawa RR, Kristiansen VB, Albrechtsen NJW, Gluud LL, et al. Effects of Roux-en-Y gastric bypass and sleeve gastrectomy on non-alcoholic fatty liver disease: A 12-month follow-up study with paired liver biopsies. J Clin Med. 2021;10(17):3783.
10. Pinyopornpanish K, Leerapun A, Pinyopornpanish K, Chattipakorn N. Effects of metformin on hepatic steatosis in adults with nonalcoholic fatty liver disease and diabetes: Insights from the cellular to patient levels. Gut Liver. 2021;15(6):827–40.
11. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57.
12. Brandt A, Hernández-Arriaga A, Kehm R, Sánchez V, Jin CJ, Nier A, et al. Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine. Sci Rep. 2019;9:6668.
13. Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, et al. GLP-1 receptor agonists in non-alcoholic fatty liver disease: Current evidence and future perspectives. Int J Mol Sci. 2023;24(2):1703.
14. Mantzoros CS, Polyzos SA. Adiponectin and leptin in the diagnosis and therapy of NAFLD. Metabolism. 2021;115:154439.
15. Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism. 2020;92:67-79.
16. Boutari C, Perakakis N, Mantzoros CS. Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinol Metab (Seoul). 2020;35(1):1–14.
17. Polyzos SA, Kountouras J, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: A systematic review. Endocrinol Metab (Seoul). 2019;34(1):1–14.
18. Polyzos SA, Kountouras J, Anastasilakis AD, Triantafyllou GA, Mantzoros CS. Activin A and follistatin in patients with nonalcoholic fatty liver disease. Metabolism. 2019;98:1–7.
19. Polyzos SA, Kountouras J, Anastasilakis AD, Geladari EV, Mantzoros CS. Irisin in patients with nonalcoholic fatty liver disease. Metabolism. 2019;98:1–7.
20. Kouvari M, Boutari C, Chrysohoou C, Fragkopoulou E, Antonopoulou S. Mediterranean diet is inversely associated with steatosis and fibrosis and decreases ten-year diabetes and cardiovascular risk in NAFLD subjects: Results from the ATTICA prospective cohort study. Clin Nutr. 2020;39(12):3610–6.
21. Lee S, Ko BJ, Gong Y, Han K, Lee A. Self-reported eating speed in relation to non-alcoholic fatty liver disease in adults. Eur J Nutr. 2020;59(5):2223–30.
22. Perakakis N, Polyzos SA, Yazdani A, Sala-Vila A, Kountouras J. Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: A proof of concept study. Metabolism. 2020;111:154329.
23. Petagine L, Zariwala MG, Patel VB, et al. Non-alcoholic fatty liver disease: Immunological mechanisms and current treatments. World J Gastroenterol. 2023;29(32):4831–50.
24. Fa P, Ke BG, Dupre A, Tsung A, Zhang H, et al. The implication of neutrophil extracellular traps in nonalcoholic fatty liver disease. Front Immunol. 2023;14:1292679.
25. Cho YE, Kim Y, Kim SJ, Lee H, Hwang S, et al. Overexpression of interleukin-8 promotes the progression of fatty liver to nonalcoholic steatohepatitis in mice. Int J Mol Sci. 2023;24(20):15489.
26. Waller KJ, Saihi H, Li W, Brindley JH, De Jong A, Syn WK, et al. Single-cell phenotypes of peripheral blood immune cells in early and late stages of non-alcoholic fatty liver disease. Clin Mol Hepatol. 2023;29(2):417–32.
27. Moreno-Fernandez ME, Giles DA, Oates JR, Chan CC, Damen M, Doll JR, et al. PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metab. 2021;33(6):1187–1204.e9.
28. Ma DW, Ha J, Yoon KS, Kang I, Choi TG, Kim SS, et al. Innate immune system in the pathogenesis of non-alcoholic fatty liver disease. Nutrients. 2023;15(9):2068.
29. Yin X, Guo X, Liu Z, Wang J, et al. Advances in the diagnosis and treatment of non-alcoholic fatty liver disease. Int J Mol Sci. 2023;24(3):2844.
30. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023.
31. Younossi ZM, Stepanova M, Ong JP, Jacobson IM, Bugianesi E, Duseja A, et al. Global burden of NAFLD and NASH: Trends, forecasts, and policy implications. Nat Rev Gastroenterol Hepatol. 2023;20(4):226–36.
32. Francque S, et al. NAFLD and the metabolic syndrome: Mechanistic insights and clinical perspectives. J Hepatol. 2023;78(1):14–25.
33. Juanola O, Martínez-López S, Francés R, González-Navajas JM, et al. Metabolic syndrome and NAFLD: Pathophysiology and molecular mechanisms. Front Med (Lausanne). 2021;8:713409.
34. Bence KK, Birnbaum MJ, et al. Metabolic dysfunction and NAFLD: The role of insulin resistance and hypertension. Annu Rev Physiol. 2021;83:361–83.
35. Tilg H, Adolph TE, Moschen AR, et al. Insulin resistance and non-alcoholic fatty liver disease. Nat Rev Endocrinol. 2021;17(5):248–61.
36. Teng Y, Zhang J, Liu Y, et al. Association of HOMA-IR with liver histology in NAFLD: Evidence from a multicenter study. Diabetes Metab Syndr Clin Res Rev. 2022;16(2):102380.
37. Tilg H, Adolph TE, Dudek M, et al. Dyslipidemia and NAFLD: Causes, consequences, and treatment strategies. J Hepatol. 2021;75(4):946–60.
38. Safari Z, Gérard P, et al. Uric acid and hepatic steatosis: The role of oxidative stress. Nutrients. 2019;11(8):1987.
39. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I, et al. The role of hepatic protein synthesis and immune dysregulation in NASH pathogenesis. Cell. 2021;184(3):552–68.
40. Tilg H, Adolph TE, Trauner M, et al. Inflammation in NAFLD: Current concepts and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2022;19(8):501–12.
41. Wajsbrot NB, Leite NC, Salles GF, Villela-Nogueira CA, et al. Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring. World J Hepatol. 2022;14(5):951–65.
42. Puri P, Sanyal AJ, et al. Lipotoxicity and inflammation in NAFLD: Mechanistic insights and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2022;19(5):294–310.
43. Lee JY, Ko EJ, et al. Impact of obesity-induced inflammation on liver immunity and NAFLD. J Inflamm Res. 2023;16:359–74.
44. Choudhary NS, Sarin SK, et al. Hepatokines in NAFLD: Emerging link between metabolism and immunity. Clin Liver Dis. 2022;20(3):114–22.
45. Martínez-Castillo M, Muñoz LE, et al. Role of extracellular vesicles in liver-immune communication in NAFLD. Cell Commun Signal. 2023;21(1):34.
46. Gebru YA, Gupta H, Kim HS, Eom JA, Kwon GH, Park E, et al. T cell subsets and natural killer cells in the pathogenesis of nonalcoholic fatty liver disease. Int J Mol Sci. 2021;22(22):12190.
47. Wang J, Chen J, Li J, Li Z, Zhang Y, et al. Role of CD8+ T cells in the progression of non-alcoholic steatohepatitis. Hepatol Res. 2023;53(1):12–22.
48. Wu L, Qiu L, Yuan M, Wang Y, Wang D, Li C, et al. Crosstalk between immune cells and gut microbiota in NAFLD. Front Immunol. 2022;13:857377.
49. Li Z, Yuan Q, Wang H, et al. IL-17-producing cells in NAFLD: Friends or foes? Immunol Rev. 2023;316(1):112–25.
50. Zhao M, Luo L, Xu L, et al. The role of liver-resident immune cells in the progression of NAFLD. Cell Mol Immunol. 2023;20(3):189–202.
51. Yu R, Tan H, Wang J, Wei H, et al. NK cell dysfunction in obesity and NAFLD: Mechanisms and therapeutic implications. Front Endocrinol (Lausanne). 2022;13:898243.
52. Chen Y, Chen J, Gong J, et al. Adaptive immunity in liver fibrosis of NAFLD: A comprehensive review. Cells. 2023;12(3):417.
53. Liu J, Zhang W, Zhao H, Sun Y, et al. Innate immune mechanisms linking metabolic stress to hepatic inflammation in NAFLD. Nat Rev Immunol. 2023;23(2):112–26.
54. Zhu L, Liu J, Ma X, Wang J, et al. Interactions between gut microbiota, immune system, and NAFLD: A triangular relationship. Pharmacol Res. 2023;189:106703.
55. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, et al. Association of immune markers with NAFLD: A meta-analysis. JAMA Netw Open. 2023;6(2):e230197.
56. Fang M, Zhou H, Xu J, Zhang X, et al. The NLRP3 inflammasome in hepatic steatosis and fibrosis. Front Pharmacol. 2022;13:881532.
57. Chen X, Wang Y, Liang H, Chen H, et al. NLRP3 inflammasome-mediated pyroptosis in NAFLD. Front Cell Dev Biol. 2022;10:928404.
58. Gao Y, Li T, Lu W, et al. The interplay of Kupffer cells and hepatic stellate cells in NAFLD. Int J Mol Sci. 2022;23(15):8295.
59. Qiao J, Li Y, Chen J, Wang X, et al. Mitochondrial dysfunction and innate immunity in NAFLD. Redox Biol. 2022;51:102277.
60. Zhang S, Xu H, Liu J, et al. Crosstalk between hepatocytes and immune cells in NAFLD. Biomed Pharmacother. 2023;162:114565.
2. Abenavoli L, Boccuto L, Federico A, Dallio M, Loguercio C, Di Renzo L, et al. Diet and non-alcoholic fatty liver disease: The Mediterranean way. Int J Environ Res Public Health. 2019;16(17):3011.
3. Wijarnpreecha K, Aby ES, Ahmed A, Kim D. Evaluation and management of extrahepatic manifestations of nonalcoholic fatty liver disease. Clin Mol Hepatol. 2020;26(2):168–78.
4. Samuel VT, Shulman GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 2018;27(1):22–41.
5. Tanase DM, Gosav EM, Petrov D, Jucan AE, Lacatusu CM, Floria M, et al. Involvement of ceramides in non-alcoholic fatty liver disease (NAFLD) atherosclerosis (ATS) development: Mechanisms and therapeutic targets. Diagnostics (Basel). 2021;11(11):2053.
6. Pouwels S, Sakran N, Graham Y, Leal A, Pintar T, Yang W, et al. Non-alcoholic fatty liver disease (NAFLD): A review of pathophysiology, clinical management, and effects of weight loss. BMC Endocr Disord. 2022;22:63.
7. Ali A, Amin MJ, Ahmed MU, Taj A, Aasim M, Tabrez E. Frequency of non-alcoholic fatty liver disease (NAFLD) and its associated risk factors among Type-2 diabetics. Pak J Med Sci. 2022;38(1):28–33.
8. Cermelli S, Ruggieri A, Marrero JA, Ioannou GN, Beretta L. Circulating microRNAs in patients with chronic hepatitis C and non-alcoholic fatty liver disease. PLoS One. 2011;6(8):e23937.
9. Pedersen JS, Rygg MO, Serizawa RR, Kristiansen VB, Albrechtsen NJW, Gluud LL, et al. Effects of Roux-en-Y gastric bypass and sleeve gastrectomy on non-alcoholic fatty liver disease: A 12-month follow-up study with paired liver biopsies. J Clin Med. 2021;10(17):3783.
10. Pinyopornpanish K, Leerapun A, Pinyopornpanish K, Chattipakorn N. Effects of metformin on hepatic steatosis in adults with nonalcoholic fatty liver disease and diabetes: Insights from the cellular to patient levels. Gut Liver. 2021;15(6):827–40.
11. Chalasani N, Younossi Z, Lavine JE, Charlton M, Cusi K, Rinella M, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–57.
12. Brandt A, Hernández-Arriaga A, Kehm R, Sánchez V, Jin CJ, Nier A, et al. Metformin attenuates the onset of non-alcoholic fatty liver disease and affects intestinal microbiota and barrier in small intestine. Sci Rep. 2019;9:6668.
13. Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, et al. GLP-1 receptor agonists in non-alcoholic fatty liver disease: Current evidence and future perspectives. Int J Mol Sci. 2023;24(2):1703.
14. Mantzoros CS, Polyzos SA. Adiponectin and leptin in the diagnosis and therapy of NAFLD. Metabolism. 2021;115:154439.
15. Polyzos SA, Kountouras J, Mantzoros CS. Adipokines in nonalcoholic fatty liver disease. Metabolism. 2020;92:67-79.
16. Boutari C, Perakakis N, Mantzoros CS. Association of adipokines with development and progression of nonalcoholic fatty liver disease. Endocrinol Metab (Seoul). 2020;35(1):1–14.
17. Polyzos SA, Kountouras J, Mantzoros CS. Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: A systematic review. Endocrinol Metab (Seoul). 2019;34(1):1–14.
18. Polyzos SA, Kountouras J, Anastasilakis AD, Triantafyllou GA, Mantzoros CS. Activin A and follistatin in patients with nonalcoholic fatty liver disease. Metabolism. 2019;98:1–7.
19. Polyzos SA, Kountouras J, Anastasilakis AD, Geladari EV, Mantzoros CS. Irisin in patients with nonalcoholic fatty liver disease. Metabolism. 2019;98:1–7.
20. Kouvari M, Boutari C, Chrysohoou C, Fragkopoulou E, Antonopoulou S. Mediterranean diet is inversely associated with steatosis and fibrosis and decreases ten-year diabetes and cardiovascular risk in NAFLD subjects: Results from the ATTICA prospective cohort study. Clin Nutr. 2020;39(12):3610–6.
21. Lee S, Ko BJ, Gong Y, Han K, Lee A. Self-reported eating speed in relation to non-alcoholic fatty liver disease in adults. Eur J Nutr. 2020;59(5):2223–30.
22. Perakakis N, Polyzos SA, Yazdani A, Sala-Vila A, Kountouras J. Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: A proof of concept study. Metabolism. 2020;111:154329.
23. Petagine L, Zariwala MG, Patel VB, et al. Non-alcoholic fatty liver disease: Immunological mechanisms and current treatments. World J Gastroenterol. 2023;29(32):4831–50.
24. Fa P, Ke BG, Dupre A, Tsung A, Zhang H, et al. The implication of neutrophil extracellular traps in nonalcoholic fatty liver disease. Front Immunol. 2023;14:1292679.
25. Cho YE, Kim Y, Kim SJ, Lee H, Hwang S, et al. Overexpression of interleukin-8 promotes the progression of fatty liver to nonalcoholic steatohepatitis in mice. Int J Mol Sci. 2023;24(20):15489.
26. Waller KJ, Saihi H, Li W, Brindley JH, De Jong A, Syn WK, et al. Single-cell phenotypes of peripheral blood immune cells in early and late stages of non-alcoholic fatty liver disease. Clin Mol Hepatol. 2023;29(2):417–32.
27. Moreno-Fernandez ME, Giles DA, Oates JR, Chan CC, Damen M, Doll JR, et al. PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metab. 2021;33(6):1187–1204.e9.
28. Ma DW, Ha J, Yoon KS, Kang I, Choi TG, Kim SS, et al. Innate immune system in the pathogenesis of non-alcoholic fatty liver disease. Nutrients. 2023;15(9):2068.
29. Yin X, Guo X, Liu Z, Wang J, et al. Advances in the diagnosis and treatment of non-alcoholic fatty liver disease. Int J Mol Sci. 2023;24(3):2844.
30. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023.
31. Younossi ZM, Stepanova M, Ong JP, Jacobson IM, Bugianesi E, Duseja A, et al. Global burden of NAFLD and NASH: Trends, forecasts, and policy implications. Nat Rev Gastroenterol Hepatol. 2023;20(4):226–36.
32. Francque S, et al. NAFLD and the metabolic syndrome: Mechanistic insights and clinical perspectives. J Hepatol. 2023;78(1):14–25.
33. Juanola O, Martínez-López S, Francés R, González-Navajas JM, et al. Metabolic syndrome and NAFLD: Pathophysiology and molecular mechanisms. Front Med (Lausanne). 2021;8:713409.
34. Bence KK, Birnbaum MJ, et al. Metabolic dysfunction and NAFLD: The role of insulin resistance and hypertension. Annu Rev Physiol. 2021;83:361–83.
35. Tilg H, Adolph TE, Moschen AR, et al. Insulin resistance and non-alcoholic fatty liver disease. Nat Rev Endocrinol. 2021;17(5):248–61.
36. Teng Y, Zhang J, Liu Y, et al. Association of HOMA-IR with liver histology in NAFLD: Evidence from a multicenter study. Diabetes Metab Syndr Clin Res Rev. 2022;16(2):102380.
37. Tilg H, Adolph TE, Dudek M, et al. Dyslipidemia and NAFLD: Causes, consequences, and treatment strategies. J Hepatol. 2021;75(4):946–60.
38. Safari Z, Gérard P, et al. Uric acid and hepatic steatosis: The role of oxidative stress. Nutrients. 2019;11(8):1987.
39. Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I, et al. The role of hepatic protein synthesis and immune dysregulation in NASH pathogenesis. Cell. 2021;184(3):552–68.
40. Tilg H, Adolph TE, Trauner M, et al. Inflammation in NAFLD: Current concepts and therapeutic implications. Nat Rev Gastroenterol Hepatol. 2022;19(8):501–12.
41. Wajsbrot NB, Leite NC, Salles GF, Villela-Nogueira CA, et al. Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring. World J Hepatol. 2022;14(5):951–65.
42. Puri P, Sanyal AJ, et al. Lipotoxicity and inflammation in NAFLD: Mechanistic insights and therapeutic targets. Nat Rev Gastroenterol Hepatol. 2022;19(5):294–310.
43. Lee JY, Ko EJ, et al. Impact of obesity-induced inflammation on liver immunity and NAFLD. J Inflamm Res. 2023;16:359–74.
44. Choudhary NS, Sarin SK, et al. Hepatokines in NAFLD: Emerging link between metabolism and immunity. Clin Liver Dis. 2022;20(3):114–22.
45. Martínez-Castillo M, Muñoz LE, et al. Role of extracellular vesicles in liver-immune communication in NAFLD. Cell Commun Signal. 2023;21(1):34.
46. Gebru YA, Gupta H, Kim HS, Eom JA, Kwon GH, Park E, et al. T cell subsets and natural killer cells in the pathogenesis of nonalcoholic fatty liver disease. Int J Mol Sci. 2021;22(22):12190.
47. Wang J, Chen J, Li J, Li Z, Zhang Y, et al. Role of CD8+ T cells in the progression of non-alcoholic steatohepatitis. Hepatol Res. 2023;53(1):12–22.
48. Wu L, Qiu L, Yuan M, Wang Y, Wang D, Li C, et al. Crosstalk between immune cells and gut microbiota in NAFLD. Front Immunol. 2022;13:857377.
49. Li Z, Yuan Q, Wang H, et al. IL-17-producing cells in NAFLD: Friends or foes? Immunol Rev. 2023;316(1):112–25.
50. Zhao M, Luo L, Xu L, et al. The role of liver-resident immune cells in the progression of NAFLD. Cell Mol Immunol. 2023;20(3):189–202.
51. Yu R, Tan H, Wang J, Wei H, et al. NK cell dysfunction in obesity and NAFLD: Mechanisms and therapeutic implications. Front Endocrinol (Lausanne). 2022;13:898243.
52. Chen Y, Chen J, Gong J, et al. Adaptive immunity in liver fibrosis of NAFLD: A comprehensive review. Cells. 2023;12(3):417.
53. Liu J, Zhang W, Zhao H, Sun Y, et al. Innate immune mechanisms linking metabolic stress to hepatic inflammation in NAFLD. Nat Rev Immunol. 2023;23(2):112–26.
54. Zhu L, Liu J, Ma X, Wang J, et al. Interactions between gut microbiota, immune system, and NAFLD: A triangular relationship. Pharmacol Res. 2023;189:106703.
55. Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, et al. Association of immune markers with NAFLD: A meta-analysis. JAMA Netw Open. 2023;6(2):e230197.
56. Fang M, Zhou H, Xu J, Zhang X, et al. The NLRP3 inflammasome in hepatic steatosis and fibrosis. Front Pharmacol. 2022;13:881532.
57. Chen X, Wang Y, Liang H, Chen H, et al. NLRP3 inflammasome-mediated pyroptosis in NAFLD. Front Cell Dev Biol. 2022;10:928404.
58. Gao Y, Li T, Lu W, et al. The interplay of Kupffer cells and hepatic stellate cells in NAFLD. Int J Mol Sci. 2022;23(15):8295.
59. Qiao J, Li Y, Chen J, Wang X, et al. Mitochondrial dysfunction and innate immunity in NAFLD. Redox Biol. 2022;51:102277.
60. Zhang S, Xu H, Liu J, et al. Crosstalk between hepatocytes and immune cells in NAFLD. Biomed Pharmacother. 2023;162:114565.
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| Cytokines MicroRNA-122 NASH Non-alcoholic fatty liver disease TH17 cells | ||
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How to Cite
1.
Wang D, Zhang R, Huang H, Yin L. Immunity as Cornerstone of Non-alcoholic Fatty Liver Disease: The Contribution of Innate and Adaptive Immune Mechanisms in the Pathogenesis of the Metabolic Syndrome-related Steatohepatitis. Iran J Allergy Asthma Immunol. 2026;:1-19.
