Lamina propria interleukin 17 A aggravates natural killer T‐cell activation in autoimmune hepatitis

Abstract

Autoimmune hepatitis is an interface hepatitis characterized by the progressive destruction of the liver parenchyma, the cause of which is still obscure. Interleukin (IL)‐17A is a major driver of autoimmunity, which can be produced by innate immune cells against several intracellular pathogens. Here, we investigated the involvement of IL‐17A in a mice model of immune‐mediated hepatitis with the intestine exposed to Salmonella typhimurium. Our results showed more severe Concanavalin (Con) A‐induced liver injury and gut microbiome dysbiosis when the mice were treated with a gavage of S. typhimurium. Then, the natural killer (NK) T cells were overactivated by the accumulated IL‐17A in the liver in the Con A and S. typhimurium administration group. IL‐17A could activate NKT cells by inducing CD178 expression via IL‐4/STAT6 signaling. Furthermore, via the portal tract, the laminae propria mucosal‐associated invariant T (MAIT)‐cell‐derived IL‐17A could be the original driver of NKT cell overactivation in intragastric administration of S. typhimurium and Con A injection. In IL‐17A‐deficient mice, Con A‐induced liver injury and NKT cell activation were alleviated. However, when AAV‐sh‐mIL‐17a was used to specifically knock down IL‐17A in liver, it seemed that hepatic IL‐17a knock down did not significantly influence the liver injury. Our results suggested that, under Con A‐induction, laminae propria MAIT‐derived IL‐17A activated hepatic NKT, and this axis could be a therapeutic target in autoimmune liver disease.

Research gaps and opportunities in autoimmune hepatitis—Results of the international autoimmune hepatitis group research workshop 2022

“…Natural killer (NK) cells are crucial in the initial onset of disease, and their response is followed by adaptive T-(Th1, Th17 and cytotoxic T cells) and B-cell responses, as evidenced by liver histology and serology. [48][49][50] Innate response is subsequently followed by T-cell mediated adaptive hepatitis. These tissue destructive effector T cells are controlled by regulatory T cells (Tregs).…”

Natural Killer T (NKT) Cells in Autoimmune Hepatitis: Current Evidence from Basic and Clinical Research.

“…In Table 1, we summarized all the main studies where NKT cells were specifically investigated in murine ConA-induced hepatitis as the main experimental model of AIH [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59].…”

“…The recent study by Chen et al suggested an important role of IL-17A in ConA-related liver inflammation since this cytokine was able to induce a strong activation of NKT cells and stimulate their IL-4 production. Notably, the main source of this NKT cell-activating IL-17A was identified in the mucosal-associated invariant T (MAIT) cells residing in the gut and was triggered by a microbial agent [59]. IL-17 can also be expressed by NKT cells (as previously mentioned), and its role as an effector cytokine in liver injury has been described in a murine model of acute experimental hepatitis induced by the administration of αGalCer, characterized by a significant infiltration of neutrophils and proinflammatory monocytes [63].…”

M1 macrophage‐derived exosomes promote autoimmune liver injury by transferring long noncoding RNA H19 to hepatocytes

“…Administration of concanavalin A (ConA) has been widely recognized as an appropriate model of immune‐mediated liver injury in mice. ConA‐induced liver injury is characterized as excessive activation of T cells, natural killer T (NKT) cells, macrophages, and cytokine release, such as tumor necrosis factor‐α (TNF‐α), interferon‐gamma (IFN‐γ), and interleukin‐6 (IL‐6), which lead to hepatocyte apoptosis 3,4 . Recent studies have reported that depletion of macrophage by clodronate liposomes or gadolinium chloride alleviated ConA‐induced liver injury but did not inhibit cytokine release 5,6 .…”

“…ConA-induced liver injury is characterized as excessive activation of T cells, natural killer T (NKT) cells, macrophages, and cytokine release, such as tumor necrosis factor-α (TNF-α), interferon-gamma (IFN-γ), and interleukin-6 (IL-6), which lead to hepatocyte apoptosis. 3,4 Recent studies have reported that depletion of macrophage by clodronate liposomes or gadolinium chloride alleviated ConA-induced liver injury but did not inhibit cytokine release. 5,6 Our previous study showed that dampening macrophage necroptosis can alleviate ConA-induced liver injury by blocking TNF receptor (TNFR)-1.…”