Macrophage and inflammation in diabetes and metabolic dysfunction-associated steatotic liver disease: From mechanisms to therapeutic strategies

Table 1 Macrophage-derived mediators in metabolic dysfunction-associated steatotic liver disease and type 2 diabetes

Mediators	Sources	Function in T2D	Function in MASLD
IL-1α	Kupffer cells and recruited monocyte-derived macrophages	Promote inflammation and worsen insulin resistance and metabolic syndrome	Contribute to hepatic steatosis, inflammatory cell recruitment, fibrosis progression, and systemic insulin resistance
IL-1β	Adipose tissue macrophages and Kupffer cells	Promote β-cell inflammation and ER stress, induce β-cell apoptosis, and impair glucose-stimulated insulin secretion	Exacerbate liver inflammation and MASLD development and promote the progression from steatosis to steatohepatitis
IL-6	Adipose tissue macrophages, Kupffer cells	Contribute to systemic insulin resistance and modulate adipocyte metabolism	Promote inflammation in MASLD and hepatic acute-phase response
IL-12	Adipose tissue macrophages and Kupffer cells	Reduce glucose infusion rates and impair insulin sensitivity	Boost hepatic inflammation and insulin resistance in MASLD
IL-23	Adipose tissue macrophages and Kupffer cells	Contribute to IL-17/IL-23 axis-mediated inflammatory responses and induce metabolic stress	Promote pro-inflammatory responses mediated by IL-17/IL-23 axis and induce metabolic stress
TNF-α	Adipose tissue macrophages and Kupffer cells	Promote insulin resistance via insulin receptor substrate 1 serine phosphorylation, exacerbate β-cell dysfunction and apoptosis, and induce lipolysis	Promotes hepatocyte apoptosis, fibrosis, and inflammation in MASLD, and contribute to meta-inflammation and systemic inflammation
IL-10	M2 macrophages (alternatively activated)	Promote tissue repair and protect against insulin resistance	Promote tissue repair and reduce inflammatory progression and fibrosis in MASLD
CCL2 (MCP-1)	Macrophages, adipose tissue macrophages	Promote recruitment of circulating monocytes to adipose tissue, promote macrophage infiltration and inflammation, and exacerbate insulin resistance	Recruit circulating monocytes to adipose tissue, perpetuate macrophage infiltration and inflammation, promote hepatic macrophage accumulation and fibrosis
CCL5	Macrophages	Induce chronic inflammation in T2D	Promote MASLD and liver fibrosis progression
CXCL9	Adipose tissue macrophages and Kupffer cells	Induce chronic inflammation in adipose tissue, stimulate inflammatory cytokine production, exacerbate insulin resistance, and induce tissue damage	Exacerbate liver inflammation and fibrosis, and augment systemic insulin resistance
CXCL10	Adipose tissue macrophages, Kupffer cells, and monocyte-derived macrophages	Promote metabolic inflammation and impaired insulin signaling, contribute to systemic and local inflammation, and exacerbate insulin resistance	Promote M1 macrophage polarization and recruitment, boost chronic inflammation in MASLD, and exacerbate insulin resistance
CXCL11	Adipose tissue macrophages, adipose tissue macrophages, Kupffer cells, and monocyte-derived macrophages	Exacerbate insulin resistance and influence systemic metabolism	Boost inflammatory and fibrotic progression in MASLD/MASH and promote insulin resistance and metabolic dysregulation
CXCL16	Adipose tissue macrophages, Kupffer cells, and recruited monocyte-derived macrophages	Induce chronic inflammation and metabolic dysfunction and contribute to insulin resistance in T2D	Increase macrophage infiltration, stimulate inflammatory cytokine secretion (e.g., TNF-α), influence hepatocyte metabolism and stellate cell collagen production, and increase steatohepatitis severity and fibrosis progression

T2D: Type 2 diabetes; MASLD: Metabolic dysfunction-associated steatotic liver disease; IL: Interleukin; TNF: Tumor necrosis factor; MCP-1: Monocyte chemoattractant protein-1; MASH: Metabolic dysfunction-associated steatohepatitis.