Innate Immunity and MASLD

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications.

Keywords: MASH; MASLD; adipokines; cytokines; hepatology; inflammasome; innate immunity; liver inflammation.

Figure 1

Innate immunity and MASLD: overnutrition and a Western diet fuel obesity, lipotoxicity and adipose tissue inflammation. Cytokines and adipokines derived from the adipose tissue influence hepatic inflammation. Pathogen-associated molecular patterns derived from the gut are sensed by TLR4 and inflammasomes, inducing pro-inflammatory cytokine and chemokine production. BMDMs are recruited to the inflamed liver mainly via chemokines such as CCL2. The crosstalk between innate immune cells, cytokines and various external stimuli induces hepatic inflammation and liver fibrosis. MASH may also promote adipose tissue inflammation, further fueling metabolic diseases.