Islet Macrophages Shift to a Reparative State following Pancreatic Beta-Cell Death and Are a Major Source of Islet Insulin-like Growth Factor-1

Nackiewicz, Dominika; Dan, Meixia; Speck, Madeleine; Chow, Samuel; Chen, Yi‐Chun; Pospisilik, J. Andrew; Verchere, C. Bruce; Ehses, Jan A.

doi:10.1016/j.isci.2019.100775

Cited by 44 publications

(44 citation statements)

References 57 publications

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“…A final major implication of our study is the relevance of zebrafish. We present [11,11,16] and, on the other, they support studies in mice that macrophages promote β -cell proliferation tissue regeneration [43,44]. This seemingly dichotomous finding likely reflects the differential involvement of pro-inflammatory ("M1") and anti-inflammatory ("M2") macrophages, which are not differentiated by clodronate treatment.…”

Section: Studies Of Unanue and Colleaguessupporting

confidence: 83%

12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

Kulkarni

Piñeros

Ibrahim

et al. 2021

Preprint

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Macrophages and related myeloid cells are innate immune cells that participate in the early islet inflammation of type 1 diabetes (T1D). The inflammatory signals and antigen presentation by these cells may be inducers of the adaptive immune response that is the hallmark of T1D. The enzyme 12-lipoxygenase (12-LOX) catalyzes the formation of pro-inflammatory eicosanoids from membrane-derived phospholipids, but its role and mechanisms in the pathogenesis of islet inflammation have not been elucidated. Leveraging a model of T1D-like islet inflammation in zebrafish, we show here that macrophages contribute significantly to the loss of β-cells and the subsequent development of hyperglycemia. Depletion or inhibition of 12-LOX in this model resulted in significantly reduced macrophage infiltration into islets with preservation of β-cell mass. In mice, we deleted the gene encoding 12-LOX (Alox15) in the myeloid lineage in the non-obese diabetic (NOD) model of T1D. Myeloid cell-specific Alox15 knockout NOD mice demonstrated reduced insulitis and T-cell responses, preserved β cell mass, and almost complete protection from the development of T1D. A critical effect of 12-LOX depletion appeared secondary to a defect in myeloid cell migration, a function required for immune surveillance and tissue injury responses. This effect on migration appeared to be secondary to the loss of the chemokine receptor CXCR3. Transgenic expression of the gene encoding CXCR3 rescued the migrator defect in zebrafish 12-LOX morphants. Taken together, our results reveal a formative role for innate immune myeloid cells in the early pathogenesis of T1D and identify 12-LOX as a necessary enzyme to promote their pro-diabetogenic phenotype in the context of autoimmunity.

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Section: Studies Of Unanue and Colleaguessupporting

confidence: 83%

12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

Kulkarni

Piñeros

Ibrahim

et al. 2021

Preprint

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“…After exposure to apoptotic endocrine cells, macrophages undergo a switch in the activation state, resulting in the expression of TNFα, IL-6, and IL-10, and promote the regeneration of this specific cell type from the embryonic pancreatic epithelium, rather than promoting acinar cell development [ 26 ]. Recently, it was described that islet macrophages are the main source of insulin-like growth factor 1 (IGF-1), which is secreted following β-cell death, inducing β-cell proliferation and promoting their viability [ 27 ] ( Figure 1 ). Other growth factors released from macrophages include the transforming growth factor β (TGFβ1) and the epidermal growth factor (EGF).…”

Section: Involvement Of Macrophages In β-Cell Differentiation Promentioning

confidence: 99%

“…Increasing evidence demonstrates the occurrence of inflammation and macrophage expansion also in pancreatic islets of T2D patients [ 68 , 69 ] and of rodent models of obesity and T2D [ 27 , 70 , 71 ]. These observations are supported by clinical evidence that inhibition of IL-1β in T2D patients improves glycemia and C-peptide secretion [ 72 ].…”

Section: Macrophage Signalling In Obesity-dependent Inflammation Amentioning

confidence: 99%

Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease

Cristina

Regazzi

2021

IJMS

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Macrophages are highly heterogeneous and plastic immune cells with peculiar characteristics dependent on their origin and microenvironment. Following pathogen infection or damage, circulating monocytes can be recruited in different tissues where they differentiate into macrophages. Stimuli present in the surrounding milieu induce the polarisation of macrophages towards a pro-inflammatory or anti-inflammatory profile, mediating inflammatory or homeostatic responses, respectively. However, macrophages can also derive from embryonic hematopoietic precursors and reside in specific tissues, actively participating in the development and the homeostasis in physiological conditions. Pancreatic islet resident macrophages are present from the prenatal stages onwards and show specific surface markers and functions. They localise in close proximity to β-cells, being exquisite sensors of their secretory ability and viability. Over the years, the crucial role of macrophages in β-cell differentiation and homeostasis has been highlighted. In addition, macrophages are emerging as central players in the initiation of autoimmune insulitis in type 1 diabetes and in the low-grade chronic inflammation characteristic of obesity and type 2 diabetes pathogenesis. The present work reviews the current knowledge in the field, with a particular focus on the mechanisms of communication between β-cells and macrophages that have been described so far.

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“…In this study we found that T cells contribute to the normal islet immune cell repertoire in non-diabetic mice and humans. While macrophages comprise the majority of islet immune cells [ 10 – 14 , 40 ], B and T cells each comprise up to approximately 5% of islet immune cells in young adult mouse islets. We also found that islet T cells accumulated within islets during ageing in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Despite the paucity of T cells within pancreatic islets, these cells may still produce sufficient levels of local cytokines within the islet to influence the islet environment. Such is the case for islet macrophages, comprising only 2–10 cells per islet, which are the major source of islet IL-1β [ 6 , 15 ], and play key roles in islet development and beta-cell adaptation and expansion [ 15 – 19 , 40 , 44 ]. Islet-resident group 2 innate lymphoid cells, another rare immune population in islets, have also been shown to influence insulin secretion, indirectly via islet macrophages [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

T cells accumulate in non-diabetic islets during ageing

et al. 2021

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Background The resident immune population of pancreatic islets has roles in islet development, beta cell physiology, and the pathology of diabetes. These roles have largely been attributed to islet macrophages, comprising 90% of islet immune cells (in the absence of islet autoimmunity), and, in the case of type 1 diabetes, to infiltrating autoreactive T cells. In adipose, tissue-resident and recruited T and B cells have been implicated in the development of insulin resistance during diet-induced obesity and ageing, but whether this is paralleled in the pancreatic islets is not known. Here, we investigated the non-macrophage component of resident islet immune cells in islets isolated from C57BL/6 J male mice during ageing (3 to 24 months of age) and following similar weight gain achieved by 12 weeks of 60% high fat diet. Immune cells were also examined by flow cytometry in cadaveric non-diabetic human islets. Results Immune cells comprised 2.7 ± 1.3% of total islet cells in non-diabetic mouse islets, and 2.3 ± 1.7% of total islet cells in non-diabetic human islets. In 3-month old mice on standard diet, B and T cells each comprised approximately 2–4% of the total islet immune cell compartment, and approximately 0.1% of total islet cells. A similar amount of T cells were present in non-diabetic human islets. The majority of islet T cells expressed the αβ T cell receptor, and were comprised of CD8-positive, CD4-positive, and regulatory T cells, with a minor population of γδ T cells. Interestingly, the number of islet T cells increased linearly (R2 = 0.9902) with age from 0.10 ± 0.05% (3 months) to 0.38 ± 0.11% (24 months) of islet cells. This increase was uncoupled from body weight, and was not phenocopied by a degree similar weight gain induced by high fat diet in mice. Conclusions This study reveals that T cells are a part of the normal islet immune population in mouse and human islets, and accumulate in islets during ageing in a body weight-independent manner. Though comprising only a small subset of the immune cells within islets, islet T cells may play a role in the physiology of islet ageing.

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Islet Macrophages Shift to a Reparative State following Pancreatic Beta-Cell Death and Are a Major Source of Islet Insulin-like Growth Factor-1

Cited by 44 publications

References 57 publications

12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

12-Lipoxygenase Governs the Innate Immune Pathogenesis of Islet Inflammation and Autoimmune Diabetes

Crosstalk between Macrophages and Pancreatic β-Cells in Islet Development, Homeostasis and Disease

T cells accumulate in non-diabetic islets during ageing

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