Hiroyuki Nakashima, MD, PhD

Innate immune cells in the liver and metabolic diseases

The liver is the largest organ with a unique blood flow system in which blood from the digestive organs come together to form the portal vein and filtered before going to systemic blood flow. This unique anatomical structure is ideal for processing nutrition from the gastrointestinal tract and at the same time, provides a quite efficient environment for functioning as an immune organ. Mammalians eat a lot of foods, and digestive tracts are filled with a lot of bacteria. The portal blood flow sometimes contains harmful material such as pathogenic bacteria and viruses. Therefore, checking and eliminating the toxic substances before going to systemic blood flow is essential to keep the blood flow clean. The microscopic peripheral blood flow is also unique. Plenty of blood is passing through small canals called ‘sinusoids’ at very slow speed. There are abundant unique immune cells in this sinusoidal space, such as NK cells, NKT cells, and Kupffer cells. The configuration of these innate immune cells is specified in the liver, not in other organs. The analysis of functions and relations of these innate immune cells can be the key to elucidate the defense mechanism of mammalians including human.

On this background, I have been researching immune cells in the liver. Using an experimental hepatitis model, I revealed the function of NKT cells and macrophages both in liver damage (1, 2) and regeneration (3, 4). There are distinct two populations of macrophages in the liver (5, 6): 1) classical resident Kupffer cells with active phagocytic function, and 2) macrophages recruited from the bone marrow. In experimental hepatitis, recruited macrophages with cytokine producing activity accelerate inflammation in various experimental hepatitis models (7).

In modern medicine, the increasing morbidity of metabolic diseases is one of the most significant problems. There are a lot of people suffering from obesity, high cholesterol, and diabetes. Although the excess intake of nutrition is the main reason in these diseases, the inflammation exerts the crucial role in the pathogenesis. The excess intake of nutrition causes deterioration of immune function causing inflammatory reaction in adipose tissue which in turn, exacerbates the metabolic disease worse.

A well-known complication of metabolic disease is non-alcoholic steatohepatitis (NASH). Induction of inflammation in the fat-laden liver cause chronic hepatitis which causes cirrhosis and hepatocellular carcinoma. The pathogenic mechanism is quite similar to that of refractory obesity.
As described, the liver is functioning as a nutritional organ and immune organ. This unique configuration of functions means that the liver is the best research subject to reveal the relation of metabolism and immunity.

Previously I published that experimental liver injury is accelerated by high fat and cholesterol diet consumption 7. One of the mechanisms of this phenomenon is the increase in number and functional acceleration of recruited macrophages in the liver which can also be the mechanism of NASH (8). The LXR which is the nuclear receptor of free cholesterol, defective mice shows accelerated inflammatory reactions to the ligands for experimental hepatitis (9). These data are showing that the cascades responsible for cholesterol metabolism are closely related to the functions in immunity.

In this laboratory, lots of researchers are doing exciting and sophisticated works on cholesterol metabolism. Some of them are also related to immune function, especially macrophages. I would like to contribute to this laboratory with my experience on liver immunology.

1. Nakashima H, Kinoshita M, Nakashima M, et al. Superoxide produced by Kupffer cells is an essential effector in concanavalin A-induced hepatitis in mice. Hepatology 2008;48:1979-88.
2. Inui T, Nakashima H, Habu Y, et al. Neutralization of tumor necrosis factor abrogates hepatic failure induced by alpha-galactosylceramide without attenuating its antitumor effect in aged mice. J Hepatol 2005;43:670-8.
3. Nishiyama K, Nakashima H, Ikarashi M, et al. Mouse CD11b+Kupffer Cells Recruited from Bone Marrow Accelerate Liver Regeneration after Partial Hepatectomy. PLoS One 2015;10:e0136774.
4. Nakashima H, Inui T, Habu Y, et al. Activation of mouse natural killer T cells accelerates liver regeneration after partial hepatectomy. Gastroenterology 2006;131:1573-83.
5. Ikarashi M, Nakashima H, Kinoshita M, et al. Distinct development and functions of resident and recruited liver Kupffer cells/macrophages. J Leukoc Biol 2013;94:1325-36.
6. Kinoshita M, Uchida T, Sato A, et al. Characterization of two F4/80-positive Kupffer cell subsets by their function and phenotype in mice. J Hepatol 2010;53:903-10.
7. Nakashima H, Ogawa Y, Shono S, et al. Activation of CD11b+ Kupffer cells/macrophages as a common cause for exacerbation of TNF/Fas-ligand-dependent hepatitis in hypercholesterolemic mice. PLoS One 2013;8:e49339.
8. Nakashima H, Nakashima M, Kinoshita M, et al. Activation and increase of radio-sensitive CD11b+ recruited Kupffer cells/macrophages in diet-induced steatohepatitis in FGF5 deficient mice. Sci Rep 2016;6:34466.
9. Endo-Umeda K, Nakashima H, Komine-Aizawa S, et al. Liver X receptors regulate hepatic F4/80 (+) CD11b(+) Kupffer cells/macrophages and innate immune responses in mice. Sci Rep 2018;8:9281.