Research progress on the role and mechanism of hepatic macrophages in liver injury during acute pancreatitis_West China Medical Journal

Authors：

FANG Zhichao ¹ , LI Jiamin ² , WANG Shukai ¹ ,  SONG Liang ³

1. Second Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P. R. China;
2. Basic Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P. R. China;
3. Medical Experiment Center, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi 712046, P. R. China;

Corresponding author：

SONG Liang, Email: hasong8078@sntcm.edu.cn

Keywords：

Acute pancreatitis; hepatic macrophages; immunomodulation; inflammatory factor

DOI：

10.7507/1002-0179.202303153

Video：

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Acute pancreatitis (AP) is a gastroenterological emergency with an acute onset and a high mortality rate. The main pathogenesis of AP is pancreatic damage and excessive activation of inflammatory cells induced by multiple factors. Due to anatomical features, the liver is the first extrapancreatic organ to be attacked by high concentrations of trypsin and inflammatory mediators during AP. Hepatic macrophages have been shown to be a major source of AP-related inflammatory factors. Interventions targeting hepatic macrophages may be critical to block liver injury/failure during AP, promote tissue repair, and reduce systemic symptoms. This review summarizes the pathological role of hepatic macrophages in AP and targeted interventions to provide new ideas and approaches to resolve the pathogenesis of AP and alleviate concurrent liver injury.

Citation： FANG Zhichao, LI Jiamin, WANG Shukai, SONG Liang. Research progress on the role and mechanism of hepatic macrophages in liver injury during acute pancreatitis. West China Medical Journal, 2023, 38(8): 1252-1256. doi: 10.7507/1002-0179.202303153 Copy

1.	Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet, 2015, 386(9988): 85-96.
2.	中华医学会外科学分会胰腺外科学组. 中国急性胰腺炎诊治指南(2021). 中国实用外科杂志, 2021, 41(7): 739-746.
3.	Venkatesh K, Glenn H, Delaney A, et al. Fire in the belly: a scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol, 2023, 13: 1077414.
4.	Closa D, Bardají M, Hotter G, et al. Hepatic involvement in pancreatitis-induced lung damage. Am J Physiol, 1996, 270(Pt 1): G6-G13.
5.	Hu F, Lou N, Jiao J, et al. Macrophages in pancreatitis: mechanisms and therapeutic potential. Biomed Pharmacother, 2020, 131: 110693.
6.	Chaudhry S, Emond J, Griesemer A. Immune cell trafficking to the liver. Transplantation, 2019, 103(7): 1323-1337.
7.	Park SJ, Garcia Diaz J, Um E, et al. Major roles of kupffer cells and macrophages in NAFLD development. Front Endocrinol (Lausanne), 2023, 14: 1150118.
8.	Kulle A, Thanabalasuriar A, Cohen TS, et al. Resident macrophages of the lung and liver: the guardians of our tissues. Front Immunol, 2022, 13: 1029085.
9.	Guilliams M, Scott CL. Liver macrophages in health and disease. Immunity, 2022, 55(9): 1515-1529.
10.	Kadomoto S, Izumi K, Mizokami A. Macrophage polarity and disease control. Int J Mol Sci, 2021, 23(1): 144.
11.	Bennett H, Troutman TD, Sakai M, et al. Epigenetic regulation of kupffer cell function in health and disease. Front Immunol, 2021, 11: 609618.
12.	徐文倩, 郭敏, 王晓, 等. 急性胰腺炎肝损伤的分子机制. 临床肝胆病杂志, 2022, 38(11): 2663-2668.
13.	Grewal HP, Kotb M, el Din AM, et al. Induction of tumor necrosis factor in severe acute pancreatitis and its subsequent reduction after hepatic passage. Surgery, 1994, 115(2): 213-221.
14.	杨芳春. IL-6、IL-10 与 PCT 在重症急性胰腺炎中的价值分析. 吉首: 吉首大学, 2021.
15.	Queck A, Bode H, Uschner FE, et al. Systemic MCP-1 levels derive mainly from injured liver and are associated with complications in cirrhosis. Front Immunol, 2020, 11: 354.
16.	Peng Y, Gallagher SF, Landmann R, et al. The role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis. J Gastrointest Surg, 2006, 10(6): 837-847.
17.	Peng Y, Sigua CA, Gallagher SF, et al. Protein kinase C-zeta is critical in pancreatitis-induced apoptosis of Kupffer cells. J Gastrointest Surg, 2007, 11(10): 1253-1261.
18.	Yang R, Tenhunen J, Tonnessen TI. HMGB1 and histones play a significant role in inducing systemic inflammation and multiple organ dysfunctions in severe acute pancreatitis. Int J Inflam, 2017, 2017: 1817564.
19.	Baig MS, Roy A, Rajpoot S, et al. Tumor-derived exosomes in the regulation of macrophage polarization. Inflamm Res, 2020, 69(5): 435-451.
20.	Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol, 2018, 9: 888.
21.	Mamilos A, Winter L, Schmitt VH, et al. Macrophages: from simple phagocyte to an integrative regulatory cell for inflammation and tissue regeneration-a review of the literature. Cells, 2023, 12(2): 276.
22.	Zou M, Yang Z, Fan Y, et al. Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis. Front Immunol, 2022, 13: 988326.
23.	徐跃元, 杨上文, 潘俊娣. 重症急性胰腺炎患者肠道菌群和代谢产物的变化特征及其与病情的相关性. 中国微生态学杂志, 2022, 34(11): 1334-1337.
24.	Garg PK, Singh VP. Organ failure due to systemic injury in acute pancreatitis. Gastroenterology, 2019, 156(7): 2008-2023.
25.	Zeng Z, Surewaard BG, Wong CH, et al. CRIg Functions as a macrophage pattern recognition receptor to directly bind and capture blood-borne gram-positive bacteria. Cell Host Microbe, 2016, 20(1): 99-106.
26.	Watanabe T, Kudo M, Strober W. Immunopathogenesis of pancreatitis. Mucosal Immunol, 2017, 10(2): 283-298.
27.	Bozward AG, Ronca V, Osei-Bordom D, et al. Gut-liver immune traffic: deciphering immune-pathogenesis to underpin translational therapy. Front Immunol, 2021, 12: 711217.
28.	Stenbäck A, Meurling S, Cantar C, et al. The effect of mesenteric lymphadenectomy and Kupffer cell depletion on bacterial translocation. J Surg Res, 2002, 102(2): 207-214.
29.	Hoyos S, Granell S, Heredia N, et al. Influence of portal blood on the development of systemic inflammation associated with experimental acute pancreatitis. Surgery, 2005, 137(2): 186-191.
30.	Sendler M, Dummer A, Weiss FU, et al. Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut, 2013, 62(3): 430-439.
31.	Xu L, Yang F, Lin R, et al. Induction of m2 polarization in primary culture liver macrophages from rats with acute pancreatitis. PLoS One, 2014, 9(9): e108014.
32.	Wei S, Huang Q, Li J, et al. Taurine attenuates liver injury by downregulating phosphorylated p38 MAPK of Kupffer cells in rats with severe acute pancreatitis. Inflammation, 2012, 35(2): 690-701.
33.	Fernández-Cruz L, Sabater L, Gilabert R, et al. Native and graft pancreatitis following combined pancreas-renal transplantation. Br J Surg, 1993, 80(11): 1429-1432.
34.	Gloor B, Todd KE, Lane JS, et al. Hepatic Kupffer cell blockade reduces mortality of acute hemorrhagic pancreatitis in mice. J Gastrointest Surg, 1998, 2(5): 430-435.
35.	Ou ZB, Miao CM, Ye MX, et al. Investigation for role of tissue factor and blood coagulation system in severe acute pancreatitis and associated liver injury. Biomed Pharmacother, 2017, 85: 380-388.
36.	Frossard JL, Lenglet S, Montecucco F, et al. Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. J Clin Pathol, 2011, 64(5): 387-393.
37.	Scott CL, Zheng F, De Baetselier P, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun, 2016, 7: 10321.
38.	邓彩虹, 刘俊, 丁震, 等. Treg 及 IL-4 对重症急性胰腺炎时枯否细胞 M2 极化状态的调节作用. 胃肠病学和肝病学杂志, 2014, 23(9): 1079-1085.
39.	Song Y, Wang Y, Qi X, et al. Da-Huang-Fu-Zi-Tang ameliorates severe acute pancreatitis by elevation of M2 Kupffer cells in rats. Evid Based Complement Alternat Med, 2021, 2021: 5561216.
40.	Van Laethem JL, Marchant A, Delvaux A, et al. Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. Gastroenterology, 1995, 108(6): 1917-1922.
41.	Yuan X, Luo C, Wu J, et al. Abdominal paracentesis drainage attenuates intestinal mucosal barrier damage through macrophage polarization in severe acute pancreatitis. Exp Biol Med (Maywood), 2021, 246(18): 2029-2038.
42.	Farooq A, Hoque R, Ouyang X, et al. Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol, 2014, 307(7): G732-G740.
43.	Hoque R, Farooq A, Ghani A, et al. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology, 2014, 146(7): 1763-1774.
44.	Zhang T, Xia M, Zhan Q, et al. Sodium butyrate reduces organ injuries in mice with severe acute pancreatitis through inhibiting HMGB1 expression. Dig Dis Sci, 2015, 60(7): 1991-1999.

1. Lankisch PG, Apte M, Banks PA. Acute pancreatitis. Lancet, 2015, 386(9988): 85-96.
2. 中华医学会外科学分会胰腺外科学组. 中国急性胰腺炎诊治指南(2021). 中国实用外科杂志, 2021, 41(7): 739-746.
3. Venkatesh K, Glenn H, Delaney A, et al. Fire in the belly: a scoping review of the immunopathological mechanisms of acute pancreatitis. Front Immunol, 2023, 13: 1077414.
4. Closa D, Bardají M, Hotter G, et al. Hepatic involvement in pancreatitis-induced lung damage. Am J Physiol, 1996, 270(Pt 1): G6-G13.
5. Hu F, Lou N, Jiao J, et al. Macrophages in pancreatitis: mechanisms and therapeutic potential. Biomed Pharmacother, 2020, 131: 110693.
6. Chaudhry S, Emond J, Griesemer A. Immune cell trafficking to the liver. Transplantation, 2019, 103(7): 1323-1337.
7. Park SJ, Garcia Diaz J, Um E, et al. Major roles of kupffer cells and macrophages in NAFLD development. Front Endocrinol (Lausanne), 2023, 14: 1150118.
8. Kulle A, Thanabalasuriar A, Cohen TS, et al. Resident macrophages of the lung and liver: the guardians of our tissues. Front Immunol, 2022, 13: 1029085.
9. Guilliams M, Scott CL. Liver macrophages in health and disease. Immunity, 2022, 55(9): 1515-1529.
10. Kadomoto S, Izumi K, Mizokami A. Macrophage polarity and disease control. Int J Mol Sci, 2021, 23(1): 144.
11. Bennett H, Troutman TD, Sakai M, et al. Epigenetic regulation of kupffer cell function in health and disease. Front Immunol, 2021, 11: 609618.
12. 徐文倩, 郭敏, 王晓, 等. 急性胰腺炎肝损伤的分子机制. 临床肝胆病杂志, 2022, 38(11): 2663-2668.
13. Grewal HP, Kotb M, el Din AM, et al. Induction of tumor necrosis factor in severe acute pancreatitis and its subsequent reduction after hepatic passage. Surgery, 1994, 115(2): 213-221.
14. 杨芳春. IL-6、IL-10 与 PCT 在重症急性胰腺炎中的价值分析. 吉首: 吉首大学, 2021.
15. Queck A, Bode H, Uschner FE, et al. Systemic MCP-1 levels derive mainly from injured liver and are associated with complications in cirrhosis. Front Immunol, 2020, 11: 354.
16. Peng Y, Gallagher SF, Landmann R, et al. The role of p65 NF-kappaB/RelA in pancreatitis-induced Kupffer cell apoptosis. J Gastrointest Surg, 2006, 10(6): 837-847.
17. Peng Y, Sigua CA, Gallagher SF, et al. Protein kinase C-zeta is critical in pancreatitis-induced apoptosis of Kupffer cells. J Gastrointest Surg, 2007, 11(10): 1253-1261.
18. Yang R, Tenhunen J, Tonnessen TI. HMGB1 and histones play a significant role in inducing systemic inflammation and multiple organ dysfunctions in severe acute pancreatitis. Int J Inflam, 2017, 2017: 1817564.
19. Baig MS, Roy A, Rajpoot S, et al. Tumor-derived exosomes in the regulation of macrophage polarization. Inflamm Res, 2020, 69(5): 435-451.
20. Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol, 2018, 9: 888.
21. Mamilos A, Winter L, Schmitt VH, et al. Macrophages: from simple phagocyte to an integrative regulatory cell for inflammation and tissue regeneration-a review of the literature. Cells, 2023, 12(2): 276.
22. Zou M, Yang Z, Fan Y, et al. Gut microbiota on admission as predictive biomarker for acute necrotizing pancreatitis. Front Immunol, 2022, 13: 988326.
23. 徐跃元, 杨上文, 潘俊娣. 重症急性胰腺炎患者肠道菌群和代谢产物的变化特征及其与病情的相关性. 中国微生态学杂志, 2022, 34(11): 1334-1337.
24. Garg PK, Singh VP. Organ failure due to systemic injury in acute pancreatitis. Gastroenterology, 2019, 156(7): 2008-2023.
25. Zeng Z, Surewaard BG, Wong CH, et al. CRIg Functions as a macrophage pattern recognition receptor to directly bind and capture blood-borne gram-positive bacteria. Cell Host Microbe, 2016, 20(1): 99-106.
26. Watanabe T, Kudo M, Strober W. Immunopathogenesis of pancreatitis. Mucosal Immunol, 2017, 10(2): 283-298.
27. Bozward AG, Ronca V, Osei-Bordom D, et al. Gut-liver immune traffic: deciphering immune-pathogenesis to underpin translational therapy. Front Immunol, 2021, 12: 711217.
28. Stenbäck A, Meurling S, Cantar C, et al. The effect of mesenteric lymphadenectomy and Kupffer cell depletion on bacterial translocation. J Surg Res, 2002, 102(2): 207-214.
29. Hoyos S, Granell S, Heredia N, et al. Influence of portal blood on the development of systemic inflammation associated with experimental acute pancreatitis. Surgery, 2005, 137(2): 186-191.
30. Sendler M, Dummer A, Weiss FU, et al. Tumour necrosis factor α secretion induces protease activation and acinar cell necrosis in acute experimental pancreatitis in mice. Gut, 2013, 62(3): 430-439.
31. Xu L, Yang F, Lin R, et al. Induction of m2 polarization in primary culture liver macrophages from rats with acute pancreatitis. PLoS One, 2014, 9(9): e108014.
32. Wei S, Huang Q, Li J, et al. Taurine attenuates liver injury by downregulating phosphorylated p38 MAPK of Kupffer cells in rats with severe acute pancreatitis. Inflammation, 2012, 35(2): 690-701.
33. Fernández-Cruz L, Sabater L, Gilabert R, et al. Native and graft pancreatitis following combined pancreas-renal transplantation. Br J Surg, 1993, 80(11): 1429-1432.
34. Gloor B, Todd KE, Lane JS, et al. Hepatic Kupffer cell blockade reduces mortality of acute hemorrhagic pancreatitis in mice. J Gastrointest Surg, 1998, 2(5): 430-435.
35. Ou ZB, Miao CM, Ye MX, et al. Investigation for role of tissue factor and blood coagulation system in severe acute pancreatitis and associated liver injury. Biomed Pharmacother, 2017, 85: 380-388.
36. Frossard JL, Lenglet S, Montecucco F, et al. Role of CCL-2, CCR-2 and CCR-4 in cerulein-induced acute pancreatitis and pancreatitis-associated lung injury. J Clin Pathol, 2011, 64(5): 387-393.
37. Scott CL, Zheng F, De Baetselier P, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun, 2016, 7: 10321.
38. 邓彩虹, 刘俊, 丁震, 等. Treg 及 IL-4 对重症急性胰腺炎时枯否细胞 M2 极化状态的调节作用. 胃肠病学和肝病学杂志, 2014, 23(9): 1079-1085.
39. Song Y, Wang Y, Qi X, et al. Da-Huang-Fu-Zi-Tang ameliorates severe acute pancreatitis by elevation of M2 Kupffer cells in rats. Evid Based Complement Alternat Med, 2021, 2021: 5561216.
40. Van Laethem JL, Marchant A, Delvaux A, et al. Interleukin 10 prevents necrosis in murine experimental acute pancreatitis. Gastroenterology, 1995, 108(6): 1917-1922.
41. Yuan X, Luo C, Wu J, et al. Abdominal paracentesis drainage attenuates intestinal mucosal barrier damage through macrophage polarization in severe acute pancreatitis. Exp Biol Med (Maywood), 2021, 246(18): 2029-2038.
42. Farooq A, Hoque R, Ouyang X, et al. Activation of N-methyl-d-aspartate receptor downregulates inflammasome activity and liver inflammation via a β-arrestin-2 pathway. Am J Physiol Gastrointest Liver Physiol, 2014, 307(7): G732-G740.
43. Hoque R, Farooq A, Ghani A, et al. Lactate reduces liver and pancreatic injury in Toll-like receptor- and inflammasome-mediated inflammation via GPR81-mediated suppression of innate immunity. Gastroenterology, 2014, 146(7): 1763-1774.
44. Zhang T, Xia M, Zhan Q, et al. Sodium butyrate reduces organ injuries in mice with severe acute pancreatitis through inhibiting HMGB1 expression. Dig Dis Sci, 2015, 60(7): 1991-1999.

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