Rebecca L McCullough1, Megan R McMullen1, Dola Das1, Sanjoy Roychowdhury1, Michael G Strainic2, M Edward Medof2, Laura E Nagy3. 1. Center for Liver Disease Research, Department of Pathobiology, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA. 2. Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA. 3. Center for Liver Disease Research, Department of Pathobiology, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA. Electronic address: nagyL3@ccf.org.
Abstract
BACKGROUND: Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. METHODS: C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. RESULTS: Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. CONCLUSION: Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding.
BACKGROUND: Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. METHODS: C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. RESULTS: Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. CONCLUSION: Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding.
Authors: Christoph W Strey; Maciej Markiewski; Dimitrios Mastellos; Ruxandra Tudoran; Lynn A Spruce; Linda E Greenbaum; John D Lambris Journal: J Exp Med Date: 2003-09-15 Impact factor: 14.307
Authors: Rebecca L McCullough; Megan R McMullen; Megan M Sheehan; Kyle L Poulsen; Sanjoy Roychowdhury; Dian J Chiang; Michele T Pritchard; Juan Caballeria; Laura E Nagy Journal: Am J Physiol Gastrointest Liver Physiol Date: 2018-03-29 Impact factor: 4.052
Authors: Veronica Marin; Kyle Poulsen; Gemma Odena; Megan R McMullen; Jose Altamirano; Pau Sancho-Bru; Claudio Tiribelli; Juan Caballeria; Natalia Rosso; Ramon Bataller; Laura E Nagy Journal: J Hepatol Date: 2017-06-22 Impact factor: 25.083
Authors: Rebecca L McCullough; Megan R McMullen; Kyle L Poulsen; Adam Kim; M Edward Medof; Laura E Nagy Journal: Front Immunol Date: 2018-09-20 Impact factor: 7.561