B Cell‐Mediated Maintenance of Cluster of Differentiation 169–Positive Cells Is Critical for Liver Regeneration

The liver has an extraordinary capacity to regenerate through activation of key molecular pathways. However, central regulators controlling liver regeneration remain insufficiently studied. Here, we show that B cell–deficient animals failed to induce sufficient liver regeneration after partial hepatectomy (PHx). Consistently, adoptive transfer of B cells could rescue defective liver regeneration. B cell–mediated lymphotoxin beta production promoted recovery from PHx. Absence of B cells coincided with loss of splenic cluster of differentiation 169–positive (CD169+) macrophages. Moreover, depletion of CD169+ cells resulted in defective liver regeneration and decreased survival, which was associated with reduced hepatocyte proliferation. Mechanistically, CD169+ cells contributed to liver regeneration by inducing hepatic interleukin‐6 (IL‐6) production and signal transducer and activator of transcription 3 activation. Accordingly, treatment of CD169+ cell–depleted animals with IL‐6/IL‐6 receptor rescued liver regeneration and severe pathology following PHx. Conclusion: We identified CD169+ cells to be a central trigger for liver regeneration, by inducing key signaling pathways important for liver regeneration.

[1]  Stefan Rose-John,et al.  IL-6 pathway in the liver: From physiopathology to therapy. , 2016, Journal of hepatology.

[2]  K. Köhrer,et al.  Cooperative role of lymphotoxin β receptor and tumor necrosis factor receptor p55 in murine liver regeneration. , 2016, Journal of hepatology.

[3]  S. Howie,et al.  Acute Liver Injury Is Independent of B Cells or Immunoglobulin M , 2015, PloS one.

[4]  Y. Maehara,et al.  Laparoscopic Splenectomy with Technical Standardization and Selection Criteria for Standard or Hand-Assisted Approach in 390 Patients with Liver Cirrhosis and Portal Hypertension. , 2015, Journal of the American College of Surgeons.

[5]  Masato Tanaka,et al.  Intestinal CD169+ macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes , 2015, Nature Communications.

[6]  H. Jeong,et al.  Role of the spleen in liver regeneration in relation to transforming growth factor-β1 and hepatocyte growth factor. , 2015, The Journal of surgical research.

[7]  T. Mak,et al.  Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+ Macrophage Function during Viral Infection , 2015, Journal of Virology.

[8]  H. Fujii,et al.  Interleukin-17A plays a pivotal role after partial hepatectomy in mice. , 2013, The Journal of surgical research.

[9]  P. Taylor,et al.  Tissue-resident macrophages , 2013, Nature Immunology.

[10]  Chang-Ju Kim,et al.  Splenectomy affects the balance between hepatic growth factor and transforming growth factor-β and its effect on liver regeneration is dependent on the amount of liver resection in rats , 2012, Journal of the Korean Surgical Society.

[11]  N. Hacohen,et al.  B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity. , 2012, Immunity.

[12]  K. Klingel,et al.  Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus , 2011, Nature Immunology.

[13]  P. Murray.  Faculty Opinions recommendation of CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. , 2011 .

[14]  Yasunobu Miyake,et al.  CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. , 2011, Immunity.

[15]  Brigitte Vollmar,et al.  Splenectomy improves survival by increasing arterial blood supply in a rat model of reduced‐size liver , 2010, Transplant international : official journal of the European Society for Organ Transplantation.

[16]  M. Hashizume,et al.  Laparoscopic splenectomy may be a superior supportive intervention for cirrhotic patients with hypersplenism , 2010, Journal of gastroenterology and hepatology.

[17]  Anne-Kathrin Kienzler,et al.  B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans , 2009, Proceedings of the National Academy of Sciences.

[18]  S. Nedospasov,et al.  T cell-derived lymphotoxin regulates liver regeneration. , 2009, Gastroenterology.

[19]  Burkhard Ludewig,et al.  Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence , 2008, Nature Reviews Immunology.

[20]  M. Sibilia,et al.  The EGF receptor is required for efficient liver regeneration , 2007, Proceedings of the National Academy of Sciences.

[21]  M. Shlomchik,et al.  Attenuated liver fibrosis in the absence of B cells. , 2005, The Journal of clinical investigation.

[22]  K. Pfeffer,et al.  Contribution of the Lymphotoxin β Receptor to Liver Regeneration1 , 2005, The Journal of Immunology.

[23]  David C. Lee,et al.  Amphiregulin: an early trigger of liver regeneration in mice. , 2005, Gastroenterology.

[24]  J. Kutok,et al.  TNF Family Member B Cell-Activating Factor (BAFF) Receptor-Dependent and -Independent Roles for BAFF in B Cell Physiology1 , 2004, The Journal of Immunology.

[25]  R. V. van Lier,et al.  B Cells Are Crucial for Both Development and Maintenance of the Splenic Marginal Zone1 , 2004, The Journal of Immunology.

[26]  S. Nedospasov,et al.  Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting , 2003, Immunological reviews.

[27]  M. Puder,et al.  Partial Hepatectomy in the Mouse: Technique and Perioperative Management , 2003, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[28]  D. Green,et al.  The Lymphotoxin-β Receptor Induces Different Patterns of Gene Expression via Two NF-κB Pathways , 2002 .

[29]  A. Chervonsky,et al.  Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. , 2002, Immunity.

[30]  P. Schirmacher,et al.  Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration. , 2000, Gastroenterology.

[31]  A. Demetris,et al.  Mitosis and apoptosis in the liver of interleukin‐6–deficient mice after partial hepatectomy , 1999, Hepatology.

[32]  K. Pfeffer,et al.  The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. , 1998, Immunity.

[33]  J. Peschon,et al.  Initiation of liver growth by tumor necrosis factor: deficient liver regeneration in mice lacking type I tumor necrosis factor receptor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[34]  E. Furth,et al.  Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice , 1996, Science.

[35]  G. Michalopoulos,et al.  Population expansion, clonal growth, and specific differentiation patterns in primary cultures of hepatocytes induced by HGF/SF, EGF and TGF alpha in a chemically defined (HGM) medium , 1996, The Journal of cell biology.

[36]  David C. Lee,et al.  Liver regeneration and hepatocarcinogenesis in transforming growth factor‐α‐targeted mice , 1996 .

[37]  G. Michalopoulos.  Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. , 2010, The American journal of pathology.