Neuroimmunomodulation in human autoimmune liver disease

Abstract

Bidirectional interaction between immune and nervous systems is considered an important biological process in health and disease. However, little is known about the mechanisms involved in their interaction in the human liver. This study examines the distribution of intrahepatic NPY, SP immunoreactive (IR) nerve fibers and their antomical relationship with immunocells containing tumor necrosis factor-α (TNF-α) and nuclear factor κB (NF-κB) in patients with autoimmune hepatitis. Liver specimens were obtained from control liver and autoimmune hepatitis patients. The immunoreactivity was determined by immunohisto- and immunocytochemistry and confocal laser microscopy. In hepatitis, the number of NPY-IR and SP-IR nerve fibers increased significantly. These IR nerve fibers were in very close contact with the lymphocytes. In healthy controls, no NPY-IR, SP-IR or NF-κB IR lymphocytes and only a few TNF-α positive cells, were observed. In hepatitis, some of the lymphocytes showed immunoreactivity for SP and NPY in the portal area. Fluorescent double-labeled immunostaining revealed that in these cells NPY did not colocalize with TNF-α or NF-κB. However, some of the SP fluorescence-positive immune cells exhibited immunostaining for p65 of NF-κB, where their labeling was detected in the nuclei. Under the electronmicroscope, these cells could be identified (lymphocytes, plasmacells and mast cells). The gap between the IR nerve fibers and immunocells was 1 μm or even less. Overexpression of SP in lymphocytes may amplify local inflammation, while NPY may contribute to liver homeostasis in hepatitis. Neural immunomodulation (SP antagonists and NPY) might be a novel therapeutic concept in the management of liver inflammation.

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…For example, activation of the central amygdala (CeA) and paraventricular nucleus (PVN) corticotropin-releasing-hormone neurons control humoral immune responses in a T-cell-dependent manner by promoting splenic sympathetic output and releasing NE ( 45 ). Moreover, under the stimulation of inflammation, the content of NPY secreted by neurogenic, structural, and immune cells is elevated, regulating immune cell function in a paracrine or autocrine manner ( 46 – 48 ). Thus, endogenous NPY may serve as an immunoregulatory factor directly on NPYRs of immune cells ( Figure 2 ).…”

“…NPY-IR nerve fibers are in close contact with lymphocytes ( 46 ), and NPY produced by splenic sympathetic nerve endings facilitates nerve communication with TH+ leukocytes ( 15 ). It betokens that NPY is engaged in lymphocyte recruitment.…”

Substance P and the regulation of inflammation in infections and inflammatory bowel disease

“…Immunohistochemistry has detected SP in lymphocytes that have infiltrated the liver of patients with autoimmune hepatitis (Feher et al 2013). Leucocytederived SP may be the most important source of this neuropeptide in some chronic inflammations.…”

Neuropeptid Y és P anyag immunreaktív idegrostok és immunkompetens sejtek változása hepatitisben

“…A gyulladásos folyamatokban nemcsak az SP-tartalmú idegrostok mennyisége emelkedik meg, hanem az NPY idegrostok száma is [14]. Az NPY is befolyásolja az NK-sejtek citotoxikus aktivitását.…”

“…Korábbi fl uoreszcens kettős immunjelzéses vizsgála-tunkban az NPY IR immunsejtekben kolokalizációt sem TNF-α-val, sem NF-кB-vel nem tudtunk kimutatni. Azonban néhány SP-pozitív immunsejtben az NF-кB kolokalizációban található, ahol az immunreaktivitás a sejtek magjában volt látható [14]. A legutóbbi évtizedek eredményei azt mutatták, hogy az NF-κB az egyik olyan molekula, amelyik felelős a máj patológiás elváltozásai-ért, beleértve a hepatitist, steatosist, fi brosist és a hepatocellularis carcinomát is [18,19].…”