The bidirectional immune crosstalk in metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.

Keywords: MASH; MASLD; NAFLD; NASH; adaptive immunity; immune crosstalk; innate immunity.

Figure 1.. The contribution of innate and adaptive immune systems in MASLD and the role of bidirectional communication between the two arms.

(A) Though the activities of innate immune cells are sufficient to drive the development of metabolic dysfunction-associated steatotic liver (MASL), ablation of adaptive immune cells (e.g., recombination activating 1 [Rag1]-knockout in mice) prevents the development of metabolic dysfunction-associated steatohepatitis (MASH). (B) Long-appreciated paradigm of MASLD disease progression, in which unidirectional innate activation of adaptive immune cells provides key pathogenic signals to promote the development of MASH. (C) Proposed model in which bidirectional immune crosstalk between innate and adaptive immune cells drives full-blown MASLD pathogenesis.

Figure 2.. Immunological landscape of MASLD pathogenesis.

Hepatic immune cell function is reshaped during MASLD and contributes to disease pathogenesis. Within innate immune cells, Kupffer cells (KCs) exhibit increased activation leading to increased cytokine and chemokine secretion. However, the MASH environment increases KC death, and in turn the KC population is replaced via increased recruitment of circulating monocytes that differentiate into macrophages. KC activation also recruits neutrophils, which secrete IL-6 and granule proteins to further promote proinflammatory landscape in the liver. Dendritic cells (DCs) exhibit increased hepatic accrual and antigen presentation capacity in MASLD. Contributions of innate lymphoid cells (ILCs) are understudied, with knowledge being limited to changes in hepatic accrual – namely decreased ILC1 and increased ILC2 and ILC3. NK cells express increased level of activating receptor NKG2D and promote activation of other immune cells in the liver by increased secretion of IFNγ. The contributions of NKT cells are disease stage-dependent, secreting both pro and antiinflammatory cytokines that inhibit pathogenesis during early stages but promote disease progression in later stages. Mucosal associated invariant T (MAIT) cells exhibit increased hepatic accrual and proinflammatory/profibrogenic properties, although they have also been associated with suppression of inflammation in MASLD. Of the adaptive immune cells, the contributions of CD4⁺ T cells are the most studied. Among the canonical proinflammatory subsets, Th1 cells exhibit increased hepatic accrual and IFNγ secretion, and Th17 cells exhibit increased hepatic accrual and IL-17 secretion. Th17 cells are further differentiated towards a highly inflammatory CXCR3⁺ intrahepatic subset (ihTh17 cells) in MASH. The roles of Th2 and T_reg cells are less defined in MASLD. Profibrogenic potential of Th2 cells have been implicated in progression to cirrhosis, while hepatic accrual (and potentially their contributions towards MASLD) of T_reg cells varies depending on the disease model. CD8⁺ T cells secrete more IFNγ and TNF and exhibit higher cytotoxic activity. γδ T cells show increased hepatic accrual (only in mice) and promote CD4⁺ T cell function. B cells increase the production of proinflammatory cytokines (IL-6 and TNF) and anti-OSE antibodies.

Figure 3.. The bidirectional crosstalk between adaptive and innate immune cells and the downstream effects of each signaling pathway.

(A) Canonically appreciated receptor/ligand-driven communication pathways between adaptive and innate immune cells, and “reverse signaling” of these pathways via respective ligands. (B) Signaling pathways listed in (A) in which the receptors/ligands are expressed on the opposite arms of the immune system. (C) Canonically appreciated cytokine-driven communication pathways between adaptive and innate immune cells. (D) Signaling pathways listed in (C) in which the cytokines/receptors are expressed on the opposite arms of the immune system. Red arrow indicates increasing downstream effects. Blue arrow indicates decreasing downstream effects. Receptors, ligands, and cytokines denoted in blue indicate those expressed by adaptive immune cells. Receptors, ligands, and cytokines denoted in green indicate those expressed by innate immune cells. NO, nitric oxide; Ag, antigen; Ig, immunoglobulin; SHM, somatic hypermutation; GC, germinal center; BM, bone marrow.