Macrophage-mediated metabolic dysregulation in the pancreas: Insights from obesity

Table 1 Therapeutic strategies targeting pancreatic macrophages in obesity: Molecular mechanisms and clinical implications[22]

	Mechanism of action	Biological consequences	Therapeutic implications	Ref.
Obesity-associated pancreatic macrophage activation	Excessive free fatty acids → activation of islet macrophages → induction of metabolic reprogramming → triggering of a pro-inflammatory phenotype (Integrin alpha X (CD11c)+/major histocompatibility complex class II (MHC-II)+, secretion of IL-1β/TNF-α) → recruitment of T cell infiltration	Pancreatic inflammation and tissue destruction contribute to insulin resistance and the progression of type 2 diabetes mellitus	Caloric restriction and bariatric surgery reduce macrophage infiltration
PD-1/mTORC1 pathway	A high-fat diet activates the mTORC1 pathway in macrophages, leading to increased expression of PD-1. Elevated PD-1 suppresses macrophage phagocytic capacity and antigen presentation, creating a "metabolic-immunosuppressive" vicious cycle. PD-1/programmed cell death ligand 1 interactions further promote immune tolerance, impairing metabolic regulation and perpetuating obesity-associated pancreatic dysfunction	Creates "metabolic-immune suppression" vicious cycle	PD-1 blockade (e.g., immune checkpoint inhibitors) could restore macrophage surveillance	[22,27]
IL-1β/TNF-α secretion	Obesity triggers the infiltration of CD11b+Ly6C+ monocytes into pancreatic islets, where they differentiate into M1-polarized macrophages. These macrophages excessively secrete IL-1β and TNF-α, which directly damage β-cells by inhibiting insulin secretion, disrupting calcium homeostasis, and inducing apoptosis. These cytokines also activate NF-κB and c-Jun N-terminal Kinase pathways, amplifying islet inflammation and fibrosis	Direct β-cell toxicity and insulin secretion inhibition	Engineered probiotics expressing IL-10 may counteract inflammation	[23,28]
Microbial DNA sensing	Gut dysbiosis in obesity releases microbial DNA (e.g., bacterial CpG motifs) into circulation, which activates pancreatic macrophages via toll-like receptor 9. TLR9 signaling triggers inflammasome assembly (e.g., NLRP3), leading to IL-18 and IL-1β maturation. This sterile inflammatory response exacerbates islet damage and promotes fibrotic remodeling	Promotes islet inflammation and fibrosis	DNase I treatment or TLR9 antagonists might mitigate sterile inflammation	[23]
Sympathetic-NGF axis	Sympathetic nerve-derived NGF binds to Tropomyosin Receptor Kinase A receptors on macrophages, driving their polarization toward the anti-inflammatory M2 phenotype. M2 macrophages secrete IL-10 and TGF-β, which enhance insulin sensitivity and promote adipose tissue browning. Concurrently, NGF suppresses M1-associated genes [e.g., inducible nitric oxide synthase], mitigating inflammatory responses	Improves insulin sensitivity and induces adipose browning	Targeted NGF delivery systems (e.g., hydrogel-based) could enhance precision therapy	[23,25]
Exosomal miR-155	Adipose tissue macrophages release exosomes containing miR-155, which are taken up by pancreatic macrophages. miR-155 suppresses suppressor of cytokine signaling 1 (suppressor of cytokine signaling 1), leading to hyperactivation of signal transducer and activator of transcription 1 signaling and amplifying pro-inflammatory responses. Additionally, miR-155 inhibits β-cell proliferation by downregulating key genes (e.g., pancreatic and duodenal homeobox 1, contributing to diabetic progression	Amplifies pro-inflammatory microenvironment	Anti-miR-155 oligonucleotides (exosome-loaded) may achieve tissue-specific inhibition	[26,29]

CD11c: Integrin alpha X; MHC-II: Major histocompatibility complex class II; IL-1β: Interleukin-1 beta; TNF-α: Tumor necrosis factor-alpha; mTORC1: Mechanistic target of rapamycin complex 1; PD-1: Programmed cell death protein 1; PD-L1: Programmed cell death-ligand 1; CD11b: Integrin alpha M; Ly6C: Lymphocyte antigen 6C; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; JNK: C-Jun N-terminal kinase; TLR9: Toll-like receptor 9; NLRP3: NLR family pyrin domain containing 3; IL-18: Interleukin-18; TrkA: Tropomyosin receptor kinase A; TGF-β: Transforming growth factor-beta; NGF: Nerve growth factor; iNOS: Inducible nitric oxide synthase; miR-155: MicroRNA-155; SOCS1: Suppressor of cytokine signaling 1; STAT1: Signal transducer and activator of transcription 1; PDX1: Pancreatic and duodenal homeobox 1.