Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes

Abstract

Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone conjugated to a control IgG did not have this effect but instead exacerbated liver lipid accumulation. The low-dose anti-CD163-IgG-dexamethasone conjugate displayed no apparent systemic side effects. In conclusion, macrophage targeting by antibody-directed anti-inflammatory low-dose glucocorticoid therapy seems to be a promising approach for safe treatment of fructose-induced liver inflammation.

Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

“…In vitro experiment, using IL-4 induced M2 polarization, we found myricetin induced M2-polarized macrophage genes (Ym-1, Arg1, CD163, and IL-10) similarly IL-4-induced macrophages (Figure 6F). Noticeably, several previous studies have also demonstrated that M2 macrophages activation (Ym-1 + , CD206 + , or CD163 + ) was induced and had the potential effect on inflammatory response and fibrogenesis both in chronic liver diseases and in animal models (47,(50)(51)(52). However, it's worth to note that M2 macrophages significantly decreased at the later stage of NASH and fibrosis (51).…”

An Hb-mediated circulating macrophage contributing to pulmonary vascular remodeling in sickle cell disease

“…Specific to humans but also observed in rats, Hb bound to haptoglobin is cleared by CD163 + monocytes/ macrophages (19), resulting in Hb metabolism by HO-1 and accumulation of intracellular ferritin-bound/ free iron. Thus, staining lung tissue sections for nonheme iron deposition is a useful indicator of the cellular distribution of Hb.…”

Regulation of Hepatic Inflammation via Macrophage Cell Death

“…125 Experimental models of nonalcoholic steatohepatitis (NASH) using the methionine-choline deficient (MCD) or similar diet show recruitment of proinflammatory macrophages, presence of multiple pro-and anti-inflammatory macrophage populations and varying therapeutic effects of macrophage depletion depending on which population is targeted. [126][127][128][129] Stimuli that induce NASH experimentally appear to have characteristics similar to ethanol models in which macrophage changes are initiated with a sudden loss of Kupffer cells. Reid et al demonstrated that at day 7 of the MCD diet, mice show a significantly reduced Kupffer cell population, which was replenished by infiltrating by Ly6C low macrophages.…”