Type 1 diabetes (T1D) is an autoimmune disease caused by the immune-mediated destruction of pancreatic β-cells within the islets of Langerhans. Following β-cell demise, the resultant primary pathology is the inability to regulate the uptake of glucose, leading to systemic hyperglycemia. Secondary complications of T1D include cardiovascular disease, ketoacidosis, nephropathy, retinopathy, and increased risk of stroke and peripheral ischemia. T1D arises from local pancreatic islet inflammation. In T1D, innate immunity including macrophages may play a vital role in attracting autoreactive T-cells, finally causing islet inflammation known as 'insulitis'.

The Roles of Macrophages in T1D

Studies have indicated the possible roles of macrophages in T1D. The initiator events occur in still functional prediabetic β-cells when pathways promoting islet inflammation are triggered. The initiation of insulitis in T1D is driven by initiator stimuli, such as damage-associated and pathogen-associated molecular patterns or cytokines (interleukin 1β (IL-1β) and interferon γ (IFNγ)) binding to specific receptors on the surface of β-cells and inducing endoplasmic reticulum stress and nuclear factor kappa-B (NFκB)- and signal transducer and activator of transcription 1 (STAT1)-dependent pathways. This leads to the activation of apoptotic pathways and the expression of chemokines. Chemokines attract pro-inflammatory monocytes from the circulation that differentiate into islet macrophages which, in turn, release cytokines targeting β-cells. Apoptotic bodies and TLR ligands may also induce pro-inflammatory polarisation of islet resident macrophages. Pro-inflammatory macrophages mediate T-cell recruitment via antigen presentation and finally phagocytose damaged β-cells.

Fig.1 β-cell–macrophage communication during insulitis in T1Ds. (Cosentino, 2021)

Macrophage Function and β-cell

The role of macrophages is vital for the forming of the mass of insulin-secreting cells but is inessential for the development of glucagon secreting cells. Due to their role in the processing and presentation of β-cell antigens to autoreactive T cells, M1 macrophages are the principal macrophage subtype of focus in T1D. M1 macrophages contribute NF-kB and STAT1 activation results in caspase 1/3/9/12 activation and subsequent β-cell death. It was reported that M2 islet macrophages can secrete insulin-like growth factor 1 (IGF-1) after β-cell death, prompting β-cell proliferation and promoting their viability. M2 macrophages facilitate β-cell protection and regeneration through secretion of several growth factors (i.e., transforming growth factorβ (TGFβ), epidermal growth factor (EGF), IGF-1) in concert with endothelial cell-derived growth factors (i.e., hepatocyte growth factor (HGF), fibroblast growth factor(FGF), IGF-1).

Strategies of Targeting Macrophages in T1D

Preliminary treatments for T1D have focused on depleting or repolarizing macrophages. 1) Targeted depletion of macrophages by clodronate liposomes was shown to abolish diabetes in non-obese diabetic mice, although inflammation persisted. 2) Anti-inflammatory drugs such as dexamethasone, promote M2 phenotype by reprogramming macrophages. Efforts to suppress M1 phenotypes through the adoptive transfer of M2 macrophages reduced T1D onset in non-obese diabetic mice and reduced hyperglycemia, kidney injury, and insulitis in vitro. 3) Inhibiting the inflammatory effector functions of macrophages by monoclonal antibodies against colony-stimulating factor (CSF-1) receptors reduced diabetes incidence and promoted a regulatory pathway for autoimmune progression. To limit macrophage-derived tumor necrosis factor (TNFα) by TNF-α blockades have demonstrated clinical efficacy, but they remain controversial because of the disturbance of glycemic control. Nonetheless, targeting macrophages to treat T1D is at the infancy stage, demonstrating a wide treatment gap.

Macrophages play an important role in T1D. Identification of macrophage subtypes and their secreted factors might ultimately translate into novel therapeutic strategies for T1D. Based on an advanced Macrophage Therapeutics Development platform, Creative Biolab has been committed to the field of macrophage development. With professional and abundant experience over the decade, we provide a series of comprehensive services to meet our clients' demands.

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Reference

1. Cosentino, C.; Regazzi, R. Crosstalk between macrophages and pancreatic β-cells in islet development, homeostasis and disease. International Journal of Molecular Sciences. 2021, 22(4):1765.