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.

Table 2 Important signaling pathways regulating macrophage differentiation and function during metabolic dysfunction-associated steatotic liver disease and type 2 diabetes pathogenesis[33,122-130]

Disease	Signaling pathway	Function	Ref.
MASLD	TRIM38-HSPA5 axis	Macrophage M2 polarization	Yang et al[122]
MASH	LPS-COX-2-PGE2	Macrophage inflammation	Vahrenbrink et al[123]
MASLD	Trem2	Macrophage pyroptosis and inflammation	Xiang et al[124]
MASLD	GPNMB	Retention of liver resident Kupffer cells and rerouting monocyte differentiation to Kupffer cell-resembling macrophages	Wang et al[33]
MASLD or MASH	Notch-RBPJ	Monocyte-to-macrophage transition	Guo et al[125]
MASLD	IRF5	Immunosuppressive and anti-apoptotic function	Alzaid et al[126]
T2D	PI3K/AKT/mTOR	Macrophage M2 polarization	Yang et al[127]
T2D	STING/Mef2D	Macrophage M2 polarization	Chen et al[128]
MASH, T2D	GDF-15	Regulation of obesity	L'homme et al[129]
T2D	Calreticulin	Macrophage transformation and accumulation	Zheng et al[130]

T2D: Type 2 diabetes; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; TRIM38: Tripartite motif containing 38; HSPA5: Heat shock protein family A member 5; LPS: Lipopolysaccharide; COX-2: Cyclooxygenase 2; PGE2: Prostaglandin E2; TREM2: Triggering receptor expressed on myeloid cells 2; GPNMB: Glycoprotein non-metastatic melanoma protein b; Notch: Neurogenic locus notch homolog protein; RBPJ: Recombination signal binding protein for immunoglobulin kappa J region; IRF5: Interferon regulatory factor 5; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; Mef2D: Myocyte enhancer factor 2D; STING: Stimulator of interferon response cyclic guanosinc monophosphate-adenosine 5’-monophosphate interactor 1; GDF-15: Growth differentiation factor-15.

Table 3 Clinical trials evaluating the roles of macrophages in metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, and other metabolic disorders

Clinical trial	Study type or phase	Disease	Treatment and purpose
NCT04059068	Observational	MASLD	To identify macrophage-derived drug targets to reverse liver disease and reduce macrophage-mediated adipose tissue inflammation
NCT06950710	Observational	MASLD and hepatic ischemia-reperfusion injury	To elucidate the role and mechanisms of macrophage polarization in patients with hepatic ischemia-reperfusion injury and MASLD
NCT06571474	Observational	Obesity, MASLD, T2D	To evaluate the role of transcription factor EB in adipose tissue macrophages in regulating adipose tissue and systemic metabolic function
NCT06007404	Observational	T2D, prediabetes, insulin resistance, obesity	To better understand the role of meta-inflammatory monocytes in adolescent insulin resistance by measuring the influence of body composition, lifestyle habits, and diet
NCT02498119	Observational	T2D	To test the role of arachidonic acid metabolites in the lipid droplets of macrophages
NCT03836443	Interventional	MASLD	To determine the effect of cultured hepatocyte supernatant exposed to MASLD patient plasma on human macrophages in vitro
NCT03426111	Interventional	MASH	To evaluate macrophage function in patients treated with endoscopic gastric tubulization and lifestyle modification
NCT05681468	Interventional	T2D, prediabetes, overweight, and obesity	To test the effect of ketogenic diets on immune cell function and inflammation, including macrophages
NCT02768935	Interventional	T2D, cardiovascular complications	To test the infiltration and polarization of macrophages in patients with T2D after myocardial infarction and the role of macrophage miRNAs
NCT02330549	Phase 2	T2D and suspected MASLD	To test the effect of cenicriviroc (152 mg), CCR2 and CCR5 antagonism, on insulin sensitivity in subjects with prediabetes or T2D and suspected MASLD
NCT04521114	Phase 2	MASH	To test the effect of anti-human CCR5 monoclonal antibody leronlimab (PRO 140) on MASH
NCT03151343	Phase 3	T2D, heart disease	To test the effect of SGLT-2 inhibitor on myocardial perfusion, function, and metabolism, as well as adipose tissue macrophage infiltration
NCT02285985	Phase 4	T2D	To test the effect of DPP-4 inhibitor saxagliptin on the reduction of adipose tissue inflammation and macrophage infiltration

NCT: National clinical trials; T2D: Type 2 diabetes; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis; CCR: C-C chemokine receptor; miRNAs: MicroRNAs; SGLT-2: Sodium glucose co-transport-2; DPP-4: Dipeptidyl peptidase 4.