Background:The mechanisms triggering nonalcoholic steatohepatitis (NASH) remain poorly defined. Results: Kupffer cells are the first responding cells to hepatocyte injuries, leading to TNF␣ production, chemokine induction, and monocyte recruitment. The silencing of TNF␣ in myeloid cells reduces NASH progression. Conclusion: Increase of TNF␣-producing Kupffer cells is crucial for triggering NASH via monocyte recruitment. Significance: Myeloid cells-targeted silencing of TNF␣ might be a tenable therapeutic approach.

Non-alcoholic steatohepatitis (NASH) affects 3–5% of the U. S. population having severe clinical complications to the development of fibrosis and end-stage liver diseases such as cirrhosis and hepatocellular carcinoma. A critical cause of NASH is chronic systemic inflammation promoted by innate immune cells such as liver macrophages (Mϕ) and natural killer (NK) cells. However, little is known about how the crosstalk between Mϕ and NK cells contributes to regulate NASH progression to fibrosis. In this report, we demonstrate that NKp46+ cells play an important role in preventing NASH progression to fibrosis by regulating M1/M2 polarization of liver Mϕ. Using a murine model of NASH, we demonstrate that DX5+NKp46+ NK cells are increased during disease and play a role in polarizing Mϕ toward M1-like phenotypes. This NK’s immunoregulatory function depends on the production of IFN-γ but not by granzyme-mediated cytolytic activity. Notably, depletion of NKp46+ cells promote the development of fibrosis with increased expression of profibrogenic genes as well as skewed M2 Mϕ phenotypes in hepatic tissues. Conclusion NK cell-derived IFN-γ may be essential for maintaining a balanced inflammatory environment that promotes tissue integrity and limiting NASH progression to fibrosis.

We have examined the pathogenic role of increased complement expression and activation during kidney fibrosis. Here, we show that PDGFRβ-positive pericytes isolated from mice subjected to obstructive or folic acid injury secrete C1q. This was associated with increased production of proinflammatory cytokines, extracellular matrix components, collagens, and increased Wnt3a-mediated activation of Wnt/β-catenin signaling, which are hallmarks of myofibroblast activation. Real-time PCR, immunoblots, immunohistochemistry, and flow cytometry analysis performed in whole kidney tissue confirmed increased expression of C1q, C1r, and C1s as well as complement activation, which is measured as increased synthesis of C3 fragments predominantly in the interstitial compartment. Flow studies localized increased C1q expression to PDGFRβ-positive pericytes as well as to CD45-positive cells. Although deletion of C1qA did not prevent kidney fibrosis, global deletion of C3 reduced macrophage infiltration, reduced synthesis of C3 fragments, and reduced fibrosis. Clodronate mediated depletion of CD11bF4/80 high macrophages in UUO mice also reduced complement gene expression and reduced fibrosis. Our studies demonstrate local synthesis of complement by both PDGFRβ-positive pericytes and CD45-positive cells in kidney fibrosis. Inhibition of complement activation represents a novel therapeutic target to ameliorate fibrosis and progression of chronic kidney disease.