Basic Science and Translational Medicine in Tissue Injury and Regeneration
Our research interests lie on the fine fissure between the physiological and pathophysiological responses to tissue injury, loss and regeneration. For the last 20 years my students and I have been privileged to participate in a close scientific collaboration with Prof. Stefan Rose-John and colleagues at the University of Kiel, in Germany, in studying the roles of interleukin 6 signaling, which we have used to explore specific examples tissue loss and tissue regeneration. Using our molecular tools… Our aim is to explore basic science of these processes and to promote translational medicine.
These are some of the scientific advances our research has produced:
- Discovery of an IL6-dependent mechanism that promotes genomic instability and micronuclei formation and heralds accelerated hepatocarcinogenesis following liver resection
- Identification of the roles of IL-6 and STAT3 signaling in the prevention of liver cancer on a background of chronic-inflammation
- Identification of an inherent function of IL-6 trans-signaling in the prevention of mature-onset obesity, metabolic syndrome and hepatosteatosis.
- Identification of a role of cellular senescence in radiation-induced loss of salivary gland function and xerostomia in mice and human patients
- Discovery of molecular signaling mechanisms driving radiation-induced alopecia and radiodermatitis
- Elucidation of the roles of IL-6 and IL-6 trans-signaling in tissue injury and regeneration: liver regeneration
- Determination of a crucial and opposing roles of IL-6 and IL-6 trans-signaling in the development and prevention of acute kidney injury
IL-6-Dependent genomic instability heralds accelerated hepatocarcinogenesis
Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality. Partial hepatectomy in Mdr2 knockout (Mdr2-/-) mice accelerates hepatocarcinogenesis. We demonstrated that liver regeneration in the Mdr2-/- mice, which involves hepatocytes containing DNA damage (γH2AX, 53BP1), strongly enhances genomic instability manifested by a striking IL-6-mediated increase in hepatocytes with micronuclei. This enhanced genomic instability heralds the accelerated development of liver cancer in these mice and can be prevented by IL6 blockade. Lanton et al. Hepatology 65:1600, 2017.
Salivary Gland Function and Xerostomia Radiation-Induced Alopecia and Radiodermatitis
IL-6 and cellular senescence mediate radiation-induced salivary gland hypofunction, dermatitis and hair loss
Off-target effects of radiotherapy can often cause injury and loss of function to healthy tissues. We identified cellular senescence as a major inherent driver of radiation-induced salivary gland hypofunction for which IL-6 and the SASP are crucial mediators. Conversely, pretreatment with IL-6 can also prevent senescence by a mechanism of enhanced DNA repair. Similarly, IL-6 and CCR6 are key mediators of radiodermatitis and alopecia and can be prevented by inhibitors of IL6/STAT3 signaling. Marmary et al. Cancer Res. 76:1170, 2016. And Paldor et al. (manuscript in revision, 2018)
IL-6 trans-signaling promotes early liver regeneration
Following PH, circulating levels of kupffer cell derived IL-6, and sIL-6R, which may originate from infiltrating neutrophils, increase significantly and cooperate with growth factors to enhance early hepatocyte proliferation through PI3K/AKT activation. Blocking of IL-6 trans-signaling by sgp130Fc reduces PI3K/AKT activation, and delays hepatocyte proliferation. Nechemia-Arbely et al., J. Hepatology 54:922-929, 2011.
Acute Kidney Injury
The role of IL-6 and gp130 signaling in AKI
(A) IL-6 stimulates an immune mediated inflammatory response involving neutrophil infiltration to the renal parenchyma driving renal injury. However, prior therapeutic intervention with Hyper-IL-6 induces resistance to injury in tubular epithelial cells by activation of STAT3 and up-regulation of redox-related genes including HO-1 and Ref-1. These proteins may collaborate to prevent oxidative stress and reduce renal injury. (B) A model for the dual role of gp-130 signaling in AKI. IL-6 promotes neutrophil infiltration via membrane bound IL-6R and exacerbates renal injury. Neutrophils can release their membrane bound IL-6R by shedding and promote protection by gp130 trans-signaling. This provides the basis of the dual role of IL-6 and IL-6/sIL-6R in tissue damage and protection. Nechemia-Arbely et al., J Am Soc Nephrol 19:1106–1115, 2008.