Abstract
Diabetes is a complex of genetic, metabolic, and autoimmune disorders that are characterized by hyperglycemia. Elevated apoptotic cell count following defective clearance of dead cells that can cause chronic inflammation is a hallmark of the diabetic wound. Effective dead cell clearance is a prerequisite for rapid inflammation resolution and successful recovery. Efferocytosis is a multistep process in which phagocytes engulf the dead cells. Cell body elimination is of great significance in disease and homeostasis. Recent research has clarified that diabetic wounds have an enhanced load of the apoptotic cell, which is partly attributed to the dysfunction of macrophages in apoptotic clearance at the site of the diabetic wounds. In the current work, we highlight the pathways implicated in efferocytosis, from the diagnosis of apoptotic cells to the phagocytic swallowing and the homeostatic resolution, and explain the possible pathophysiological episodes occurring when the proceeding is abrogated. Also, we describe the last development in the management of inflammation in diabetes wound and future directions of surveillance.
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Introduction
Diabetes, a multifactorial disorder in metabolism, occurs when the insulin production by the pancreas is insufficient, or the body cannot effectively use the insulin [1]. The common characteristic of this condition is hyperglycemia chronically because of fault in carbohydrates, fat, and protein metabolism. Persistent hyperglycemia causes multiple organ dysfunction, including bone, nerves, blood vessels, eyes, kidneys, and heart [2, 3]. Diabetes has three main classes, including Type 1 diabetes mellitus (T1DM), Type 2diabete Mellitus (T2M), and Gestational diabetes mellitus (GDM). Those types are created from various causes. T1DM is usually observed in people lower than 30 years old. However, it may affect older people [4]. T1DM does not fully understand but is known for failing in insulin secretion via various causes such as an autoimmune or idiopathic attack, which destroys beta cells of Langerhans islets located in the pancreas [5]. Hence, curing it is principally accomplished by insulin replacement. Another diabetes type (T2M) is characterized by relative insulin deficiency caused by the defect in the beta-cell of the pancreas and insulin resistance [6]. Cardiovascular disease (CVD) is the main etiology of T2M-related diseases and deaths and requires severe management of blood pressure, glucose, and fat to minimize the risk of disease progression [7, 8]. Gestational diabetes is becoming more prevalent, together with type 2 diabetes and fatness [9]. Hyperglycemia, which develops during pregnancy, has been known for more than 50 years, but there is no universal consensus on high blood sugar levels that can be used to diagnose and treat “gestational diabetes” (GDM). Nowadays, GDM has been found to be the most prevalent medical complication during pregnancy, and the hyperglycemia outbreak has not been distinguished, and reports show that the number of young women with overt diabetes is increasing [10].
Apoptosis is a highly regulated cell death process. Both necrosis and apoptosis are the main cell death types. While necrosis is a traumatic version and accidental of cell death, apoptosis is a predefined cell suicide to particular victim cells for the greater profit of the organism. It is an ordinary physiologic process carried out in multicellular organisms [11]. Today, it has been well established that apoptosis brings benefits to the survival of multicellular organisms, whereby organisms maintain homeostasis and regulate the life cycle. Nevertheless, the remains many mysteries remain in the relevant research areas [12].
Macrophages engulf apoptotic cells in a process called efferocytosis[13]. Elimination of cellular corpses is critical in the treatment of disease and homeostasis. Through engulfment of dead cells, phagocytes, known as efferocytosis, help recycle cellular components in multicellular organisms. Autoimmune and other conditions can develop when the disposal of cell corpses is faulty. This attempt briefly reviews the relationship and mechanism of efferocytosis associated with diabetes disease. We first discuss the mechanism of efferocytosis and then explain related to diabetes in various aspects.
Mechanism of efferocytosis
Billions of cells die in the body of human beings to regulate immune responses, cell homeostasis and wound healing. Dying cells must be effectively removed to perform all these processes [14]. The clearance of dead cells, which usually occurs during human life, is termed efferocytosis [15]. Altogether, the processes of efferocytosis possess four phases: (1) The dead cells issue a “find me” signal, (2) the phagocytes are identified, and their contribution is determined in the liberation of the “eat me” signal on the cell body, (3) The dead cells are swallowed, and (4) the swallowed cells are destroyed [16].
Find-me signals
Apoptosis is physiological programmed cell death. Encapsulation of apoptotic cells in apoptotic bodies aid in the prohibition of diffusion of pro-inflammatory and inflammatory cell contents, subsequently recycling and excreting them via neighboring scavenger cells [17]. During programmed cell death, the signals are liberated by the cell into the environment to absorb the macrophages and agitate their scavenging potential of them. In this process, signaling molecules from apoptotic cells are released into the environment [18]. Apoptotic cells emit two categories of signals: extracellular vesicles and soluble molecules. ‘find-me’ Signals emitted from apoptotic cells include nucleotides, modified membrane lipids, and chemokines. The most well-known find-me are nucleotides such as uridine triphosphate and adenosine triphosphate.Apoptotic cells release these nucleotides into the environment via the pannexin-1 channel [19]. Sphingosine-1-phosphate (S1P), ATP / UTP, Lysophosphatidylcholine (LPC), and chemokines (Fractalkine) are other signals emitted by apoptotic cells [18, 20]. It should be noted that the signals of find‐me fall into four basic categories: lysophosphatidylcholine (LPC), sphingosine-1-phosphate (S1P), CX3CL1, and nucleotides [21] (Fig. 1-A).
The efficiency and role of any find-me signal depend on the type of dead cell and phagocyte [22], as well as the diversity of find-me signals, suggests inherent redundancy, thereby ensuring the macrophages to recognize dead cell bodies.
Eat me signals
Cells that are dying display the signals of eat-me on their surface, considered as the signals of ‘eat-me’ include a. lack of phospholipid asymmetry in the cell membrane [23], b. displayed LPC to the surface of dying cells attaches to Fc receptors on scavenger cells like macrophages[24], c. Display of proteins in the endoplasmic reticulum (ER) lumen on the dying cell surface and the absence of " don’t-eat-me " signals act as the signal of ‘eat-me’ [25]. Phagocytes discriminate dying cells from healthy neighbors through the signals of ‘eat-me’, which neighbors cells have the signals of ‘don’t-eat-me’. In other words, apoptotic cells issue the signals of find-me and eat‐me to detect these signals via phagocytes can accelerate their ingestion; Reciprocally, the signals of don’t‐eat‐me emitted by apoptotic cells can block their swallowing. Many investigations scrutinized the stages of phagocytosis, and each stage is specifically identified [26, 27].
Engulfment of dead cells
When a phagocyte detects a dying cell, the dead cell engulfment needs quick plasma membrane detection, and the dead cell must be encapsulated quickly in phagocytes [28]. A dynamic network of actin under the cell membrane motivates phagocytes to environmental sampling. The phagocyte begins to rearrange the actin by detecting an apoptotic cell, allowing the plasma membrane to penetrate and localize, eventually forming the phagosome. Coordinated activation of kinases, like Srk, Syk, and protein kinase C (PKC) families, and phosphatase inactivation, like SHP-1, are signaling mechanisms that differentiate the receptor by activating actin regeneration and relevant pathways based on the involved receptor [29]. The two main mechanisms involved actin reorganization within spherocytosis, converging in the major regulator, Rac1, a member of the Rho family of GTPases. Rac1 activation is mediated in the first system through LDL receptor-related protein 1 (LRP1) and adapter protein GULP [30]. Overall, several important signals contribute to the Eat-me process: phosphatidylserine (PtdSer), which interacts with BAI1 and av-beta3. Another one is calreticulin (Calr) which interacts with lipoprotein receptor-related protein 1 (LRP1) (Fig. 2-B) [31]. However, healthy cells for shielding from phagocytosis express several signals called “Don’t eat me” including CD24, CD47, and CD31. These signals could bind to several receptors on phagocytes (Siglec-10, CD31, SIRP) and prevent the efferocytosis process (Fig. 2-C) [31].
Degradation of the engulfed cells
After recognizing and trapping the dying cell, the cell body and phagosome are well organized for a ruinous ending. Following the uptake of dying cells by the scavenger cells, the phagosome incorporates with the lysosomes. Because liposomes involve many types of lipases, proteases, and nucleases, this fusion causes the digestion of phagosome cargo [32].
When phagosomes ingest dead cells, they are targeted with lysosomes via a multi-stage maturation process. Immediately after phagosome formation, a dynamin-dependent membrane fracture begins, accompanied by numerous biochemical changes in the phagosome membrane [33].
After engulfment, several signals related to efferocytosis and wound-healing are promoted and cause a change in the metabolism of the immune system, immunosuppression, wound healing, and M2-like macrophage polarization, which significantly affects the local tissue microenvironment. Several nuclear receptors (NR), particularly liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR), are stimulated in reaction to efferocytosis. In this process, apoptotic cells are immersed in LC3-associated phagocytosis (LAP) [34]. Subsequently, it fused with lysosomes and degraded efficiently. Then fatty acids productions such as 25-hydroxysterol active PPAR and LXR. This nuclear receptor induces the transcription of immunosuppressive cytokines, including TGF-beta1, IL-13, and IL-10. They also indicated that transcribed pro-efferocytosis machinery comprises Gas6, MertK, and Rac1 (Fig. 2) [34].
Impact of abnormal efferocytosis on diabetes
One of the major sources of autoantigens in diabetes is apoptotic β-cells. Autoimmune is facilitated by a high incidence of β-cell apoptosis or deficiencies in the clearance of apoptotic cells in pre-diabetes [35]. These cells transform into late apoptotic bodies and secondary necrotic cells, increasing insulitis, inflammation, and autoimmunity. If apoptotic β-cells are not removed quickly enough, they clump together, causing autoantigens to be released and inflammatory signals to be activated. On the other hand, loss of pancreatic β-cells due to abnormal efferocytosis might cause hyperglycemia and insulin insufficiency, which has been linked to the etiology of diabetes (Fig. 3) [36]. Several animal researches indicated that abnormal efferocytosis had been associated with diabetes [37, 38]. In table 1, we summarise the researches accomplished on efferocytosis and diabetes.
Factors contributing to the efferocytosis process in diabetes
Until now, numerous factors have been proposed as possible causes of diabetes. The following are some of the factors that contribute to this process:
Phagocytic oxidative stress can result in defective efferocytosis, impairing phagocytes’ ability to engulf apoptotic cells [39]. The phagocytic dysfunction in macrophages has been found as a known property of diabetes [40, 41]. Macrophages are involved in tissue regeneration and repair, which is impaired in diabetes, resulting in poor regeneration and delayed repair. This process is also affected by the microenvironment [42]. Efferocytosis is a critical cellular procedure for immune response and maintaining tissue homeostasis [43]. When tissue is injured, phagocytes swallow and clear dead cells, resulting in an efficient resolution of the inflammation [44]. Numerous studies have shown that macrophage function is impaired in diabetes and is related to prolonged inflammatory response and harmful alteration in heart regeneration, thus increasing the risk of heart defeat and altering the outcome of the disease [45]. Efferocytosis decreased in diabetic wound macrophages, resulting in the apoptotic cell accumulation in inducing inflammation response.
Efferocytosis enhancers
administering specialized pro-resolving mediators, such as maresin 1, LXA4, resolvin D1, or resolvin D2, which act as efferocytosis enhancers, improves efferocytosis while decreasing the incidence of phagocytic inflammation [46,47,48].
High glucose
high glucose is one of the key characteristics of diabetes that can lead to efferocytosis dysfunction [49].
Mannan-binding lectin (MBL) as a serum protein can trigger the complement system and reinforce the phagocytic removal of different inflammatory parameters [51]. The oligomeric C-type lectin of MBL detects specific sugar patterns on the surface of apoptotic cells [52]. In a cross-sectional study to reveal a relationship between MBL with nephropathy among T1D subjects, the concentrations of MBL were greater in the study cases suffering from macrovascular disease.As well as, the MBL has been reported to increase apoptotic cell clearance in diabetic patients [53].
Adiponectin is a hormone derived from adipocytes that exerts anti-inflammatory and anti-diabetic performances. It employs the macrophages to facilitate the early apoptotic cell uptake that is substantial for the activity of immunity [54]. Mice deficient in adiponectin (APN-KO) showed impairment in their capacity for apoptotic thymocyte clearance. This hormone opsonizes the apoptotic cells, and the adiponectin-mediated phagocytosis causes the attachment of cell corpses to calreticulin located on the surface of macrophages. In this way, adiponectin enhances its anti-diabetic properties [55].
Apolipoprotein (apo) E4
One of the pivotal risk factors is apolipoprotein (apo) E4 for diverse inflammations and metabolic problems, like Alzheimer’s disease (AD), atherosclerosis, and diabetes. The secretion of apoE4 promotes macrophage dysfunction and apoptosis by decreasing ER stress. The inflammatory responses and relevant metabolic disorders associated with polymorphism in apoE4 may be decreased by reducing ER stress in macrophages [56].
ER stress has the potential to impede the efferocytosis process [57]. In addition, it was shown that stress could develop diabetes and insulin resistance. The efferocytosis can be reinforced by the developmental endothelial locus-1 (DEL-1) via macrophage, suppressing the inflammation [58].
MERTK
it was shown that Mer tyrosine kinase (MERTK) mediates efferocytosis in atherosclerotic lesions. This gene encoded Proto-oncogene tyrosine-protein kinase MER that engulfs apoptotic cells by interacting with the phosphatidylserine-binding proteins Gas6 or Protein S, which are bridging molecules [59].
MFG-E8
A study showed that a lake MFG-E8 gene in mice causes impairment in efferocytosis. Mice deficient in MFG-E8 receiving wild-type bone marrow revealed it resolved inflammation, supported angiogenesis, and improved wound closure [50].
Erythropoietin (EPO) signaling defective is a significant cause of abnormal efferocytosis leading to type 2 diabetes. S1P generated by apoptotic cells binds to the cognate receptor on macrophages, facilitating efferocytosis via the EPO-EPO receptor-peroxisome proliferator-activated receptor-γ signaling pathway [60].
Role of interventional treatment on efferocytosis
A diabetes case report showed that administration of Rituximab could induce efferocytosis in diabetic patients. It was reported that clearance is effective in tissue B-cell [61]. Rituximab, as an anti-CD20 antibody, might accomplish its effect by inducing the effect of Fc receptor-dependent phagocytosis [62]. The multifunctional molecule of the cluster of differentiation 36 (CD36) possesses separate binding sites for various ligands like modified phospholipids, free fatty acids, and thrombospondins. The CD36 serves as a scavenger receptor on phagocytes, thereby recognizing and internalizing apoptotic cells and erythrocytes infected with falciparum malaria [63, 64]. In diabetic patients, a high concentration of LDL causes a block in the cd36 receptor, which inhibits efferocytosis [65].
The phagocytosis of apoptotic cells can be suppressed by anti-tTG (tissue transglutaminase antibody) through peritoneal macrophages extracted from the pregnant non-obese diabetic (NOD) mouse model of type I mice expressing the surface enzyme. The anti-tTG antibodies can act via a decrease in the transamidation performance and declined apoptotic cell removal via the macrophages from the pregnant diabetic mice [66].
Defective efferocytosis is associated with T1D and other autoimmune conditions [67]. The main objective of T1D prevention is to stop the autoimmune response to β-cells. Surface alterations can occur following the apoptotic β-cells in T1D, in particular exposure to the phosphatidylserine (PS) of the inner leaflet of the plasma membrane, which differentiates them from living cells and allows them to be detected by efferocytotic receptors [26, 68]. Accordingly, a synthetic protocol to stop autoimmunity against β cells has been designed, including liposomal microparticles for mimicking apoptotic cells by detecting PS and full of insulin peptides. These liposomes inhibit T1D by re-establishing specific tolerance [69].
Liposomes that mimic apoptotic β-cells inhibited βcell-related autoimmunity and impeded the experimental T1D by producing tolerogenic DC. Such liposomes are composed of the PS- a key signal of the apoptotic cell membrane, and the β-cell autoantigens. To conclude, efferocytosis can be mimicked by PS-liposomes phagocytosis, resulting in functional and phenotypic alterations in human DCs responsible for the induction of tolerance [70].
Activating resting T lymphocytes initiate apoptotic death of activated T lymphocytes. In the onset of T1D, apoptosis resistance is of great importance in the activated autoreactive T lymphocytes, which move to the pancreas from the circulation and actively destroy the insular pancreatic structures. The apoptotic reaction to Phytohemagglutinin (PHA) was the strongest for T1DM decompensation [71]. Given that T cells are mainly exposed to apoptosis in reaction to the stimulation of PHA, we can speak of the great sensitivity of active T lymphocytes to induce apoptosis in T1DM subjects. The development of autoimmune conditions has links with increased target cell apoptosis, and a defect in phagocytic removal of apoptotic cells because of a dysfunction in efferocytosis, meaning phagocytosis of apoptotic cells [72].
In the apoptosis process, a large number of apoptotic vesicles were produced [73]. In a recent study in 2021, Mesenchymal stem cells (MSCs)-derived apoptotic vesicles were employed to treat type 2 diabetes mice. They discovered that apoptotic vesicles were efferocytosed by macrophages and effectively controlled hepatic macrophage homeostasis to prevent type 2 diabetes [74]. In type 2 diabetes liver, apoptotic vesicles can promote macrophage reprogramming at the transcriptional level efferocytosis-dependent, resulting in macrophage accumulation suppression and macrophage transformation to an anti-inflammation phenotype. These authors also observed that calreticulin was exposed on the surface of apoptotic vesicles and acted as a crucial ‘eat-me’ signal driving apoptotic vesicles efferocytosis and macrophage regulatory effects at the molecular level. Notably, CRT-mediated efferocytosis of MSC-derived apoptotic vesicles aids type 2 diabetes therapy by reducing type 2 diabetes characteristics such as insulin resistance and glucose intolerance. Their data show that apoV functional efferocytosis improves type 2 diabetes by restoring hepatic macrophage homeostasis [74].
Inhibition of efferocytosis diabetic osteoporosis
DM is a persistent and chronic epidemic with associated complications increasing unabated, especially osteoporosis, which is broadly considered a new health concern worldwide [75]. A defect in bone regeneration that reduces bone mass increases bone fragility, decreases bone strength and microstructural changes in bone tissue, and leads to a high risk of fracture, known as diabetic osteoporosis [76]. Tissue-specific polykaryon macrophage that attaches to or near a bone surface is constructed via differentiating macrophage progenitor cell or a monocyte called an osteoclast (OC). As a heterogeneous cluster of immune cells, Tissue-resident macrophages have performances such as iron processing, clearance of cellular debris, and critical roles in tissue immune supervision, inflammation resolution, and infection response. Also, they play an acritical role in recruiting granulocytes into the tissue from the circulation [77, 78]. Depending on the damage grade, neutrophils cumulate in the tissue and quickly undergo apoptosis [79].
In vivo failure to remove dead cells aggravates inflammation, suggesting a prominent role of efferocytosis in moderating the inflammation in phagocytes to enhance inflammation resolution [80, 81].
Role of efferocytosis in wound healing in diabetic
The intractability of diabetic wounds can be attributed to complex parameters like prevention of angiogenesis, abnormal inflammatory responses, and dysfunction of phagocytosis by macrophages [101]. Efferocytosis is an intrinsic activity of wound macrophages [102]. Faulty efferocytosis during a diabetic situation enhances inflammatory responses and necrotic core formation, finally leading to atherosclerosis, autoimmune problems, and delayed wound healing [102]. Previously data indicated that defective efferocytosis in a mouse model of diabetes resulted in the apoptotic cell accumulation in the wounds in a maintained pro-inflammatory microenvironment [102]. In addition, it was showed hatThe efferocytosis can be successful in the progression of pro-inflammatory M1 to reparative M2 macrophage [87, 88].
As stated earlier, macrophage alteration has a pivotal performance in the induction of efferocytosis. Diabetic wounds develop a variety of inflammatory cytokines and chemokines like AGE, MCP-1, DAMPs, and IL-1β in the wound microenvironment that mutually induce NLRP3 and IL-1R1 signal pathways. These events prevent the polarization of macrophages and directly affect the efferocytosis process [103, 104] (Fig. 4). Impaired phagocytic function of macrophages (apoptotic removal performance) at the diabetic wound site; is associated with an increased count of apoptotic cells[102]. Other effective factors that increase the apoptotic cell load in the diabetic wound are the elevated level of oxidative stress, the induction of protein kinase C (PKC), and the acceleration of apoptosis affected via advanced glycation end-products (AGEs) [105, 106]. The incremental count of apoptotic cells enhanced the inflammatory response in wounds in diabetic wounds. Accurate apoptotic cell removal through the macrophages at the wound site causes the decreased secretion of diabetic wound macrophages and inflammatory cytokines [107]. Fundamental changes in bone marrow precursors, as well as pro-inflammatory wounds, cause a steady increase in the count of wound monocytes (Mo) / macrophages (Mφ) and dysregulate their phenotype, thereby resulting in faulty wound healing during diabetic situations [108, 109]. Factors involved in the normalization of macrophages’ non-healing wounds include: targeting the RAGE pathways and NLRP3 inflammasome/IL- 1β [110], and changing epigenetic modifications in the genes related to dysregulated macrophage phenotype [111]. Numerous studies showed that targeting monopoiesis can help to improve diabetic wound healing and normalize wound Mφ accumulation because increased steady-state diabetes-related monopoiesis help increase the accumulation of Mφ in diabetic wounds [112, 113]. Additionally, it revealed that PPAR-γ in wound healing via the clearance of apoptotic wound neutrophils has a significant role[114, 115]. Another research RAGE receptor regulates the count of neutrophils in diabetic wounds, reduces macrophage phagocytes’ ability, and is strictly related to defect diabetic wound healing [116] (Fig. 4).
The wound healing can be accelerated by mesenchymal stem cells (MSCs) in diabetic mice[101, 117]. Large quantities of MFG-E8 are produced by MSCs [118]. It should be noted that the secretion of MFG-E8 in granulation tissue was significantly decreased in diabetic mice when compared with healthy mice. The MFG-E8 derived from MSCs may speed the healing of diabetic wounds through the promotion of angiogenesis, the apoptotic cell removal, and the M2 macrophage infiltration, thereby blocking inflammatory cytokines at the wound site [101].
The infiltration of neutrophils is the first phase in healing the wounds, although the timely removal via macrophage engulfment, or efferocytosis, is important for effective tissue regeneration. The certain pathway for removing neutrophils in wound healing is not clear. CCN1 plays an important role in the efferocytosis of neutrophils as a bridging molecule that links phosphatidylserine, the signal of ‘eat-me’ on apoptotic cells, and αvβ3/αvβ5 integrins in macrophages to induce efferocytosis [119].
Failed wound healing is a common side effect of diabetes. The macrophages of diabetic wounds show abnormal phenotypes and dysfunctional efferocytosis that can lead to excessive accumulation of neutrophils and long-term inflammation, thus impairing wound healing [120]. Great potential can be seen for the ANXA1 N-terminal derived peptide Ac2-26 in reducing the inflammatory response and facilitating repair. Following the Ac2-26 treatment, the closure of diabetic wounds can be accelerated, the neutrophil count can be down-regulated, the angiogenesis can be improved, and the deposition of collagen can be seen [121]. Moreover, the use of Ac2-26 accelerated the recruitment of macrophages and up-regulated the number of macrophages secreting CD206 as a marker for M2 macrophages. In addition, the Ac2-26 impeded the TNF-α and IL-6 expression levels and up-regulated the TGF-β, IL-10, and VEGFA expression levels in diabetic wound healing. Accordingly, the use of Ac2-26 in diabetic wounds displays the pro-repair and anti-inflammatory impacts through a decrease in the accumulation of neutrophils and an increase in the development of M2 macrophage [122].
Insulin act as a modulator of inflammatory reactions. The insulin-degrading enzyme overexpression results in inadequate insulin levels in diabetic skin within wound healing, thereby decreasing the recovery rate of diabetic wounds [123].
Studies stated that insulin increased neutrophil apoptosis and subsequently induced macrophage polarization. Insulin re-established phagocytosis performance and enhanced the phagocytosis-induced apoptosis process in neutrophils [120]. Moreover, it is shown that insulin therapy increased efferocytosis of apoptosis neutrophils by macrophages and therefore triggered macrophages to change their polarization state to M2 from M1 [124]. To conclude, investigations confirmed that the exogenous insulin accelerated diabetic wound healing through restoration of inflammatory response.
Resolution of inflammation in efferocytosis in diabetes
T1D or insulin-dependent diabetes is an autoimmune condition in which the pancreas yields low or no insulin. Because the immune system targets the pancreatic islets and eliminates insulin-producing cells, the pancreas produces little or cannot produce insulin [125]. It has been proven that an abnormal immune response to healthy cells, tissues, and organs leads to autoimmune disease. Some of the factors that cause the breaking of tolerance in pancreatic beta-cells include Neoantigens (defective ribosomal products (DRiP), hybrid insulin peptides (HIP), posttranslational modifications(PTM), Splicing), endoplasmic reticulum (ER) stress, type 1 interferon(IFN) signature, CXCLl0, HLA upregulation, metabolites (adenosine, nutrients), hypoxia, innervations, ECM small pancreas, gluten, inflammation, Age, genetics [126, 127]. Central and peripheral tolerance are two main categories of Immune tolerance, with numerous layers of active regulation. Immature T-cells in central tolerance with very low affinity for human leukocyte antigen A (HLA) and very high reactivity to self-proteins in the thymus are removed [128]. Immune cells in peripheral tolerance may ignore and not respond to the particular antigen. The existence of molecules like PD-L1, PD-1, and CTLA-4 on self-tissue or immune cells can regulate the immune response and reduce the activation of immune cells. Other mechanisms that lead to immune tolerance include regulatory T cells (Tregs), tolerogenic dendritic cells (tolDC), and suppressing the effector immune cells [126, 129]. Tissue is damaged following the presence of autoantibodies and autoreactive B cells and T cells implicated in the pathological inflammatory response [127]. Autoimmune conditions like T1DM are developed by activating inflammatory mediators [130]. Resolvins can favorably impact this process via the stimulation of several signaling pathways. As well as resolvins can prevent the uptake of leukocytes to the inflammation site by triggering non-inflammatory monocyte employment and inducing macrophages to elevate the efferocytosis capacity towards apoptotic neutrophils [131, 132]. Following the prevention of leukocyte recruitment, inflammation resolution, pain relief, and regeneration and repair of damaged tissue can occur [133,134,135]. The risk of autoimmune diseases increases with defects in the inflammation resolution and inflammatory signals [67, 136].
Pancreatic β cells have specialized functions in the secretion and release of insulin in response to glucose. The inner environment of insulin granules causes an acidic environment that is maintained by ATPases and allows insulin to crystallize around zinc molecules [137]. Insulin crystals in lysosomes break down slowly. Following the engulfment, pathogenic crystals (calcium pyrophosphate dihydrate, monosodium urate, cysteine, and cholesterol crystals) penetrate the lysosomal membrane and induce NLRP3 inflammasome [138, 139]. Insulin crystals from β-cell efferocytosis activate the inflammasome and liberate IL-1β from the macrophages. Based on this content, preservation of macrophage lysosomal performance has been highlighted as a therapeutic intervention for the progression of diabetes [140].
Rol of microRNAs in controlling efferocytosis in diabetes
The microRNAs (miRNAs), or short non-coding RNA, can regulate the gene expression and exhibit the function in the development of various types of diabetes mellitus. It is reported that miRNAs regulate several critical genes in beta-cells and insulin. Furthermore, their level changes were introduced as a novel biomarker for diagnosing long-term diabetes complications [82, 83]. Recently, miRNAs possess pivotal performances in developing immune conditions by regulating macrophage performances. The miRNAs are complexly implicated in fine-tuning basic macrophage activities like efferocytosis, phagocytosis, inflammation, tumor progression, and tissue repair [84,85,86, 141, 142].
miR-21 is one of the miRNAs mentioned to impact efferocytosis effectively. Elevation in the level of miR-21 can convert macrophages to fibroblast-like cells. In the crosstalk of keratinocytes with myeloid cells, the extracellular vesicle (EV)-packaged miR-21 is substantial for cell conversion (Fig. 5). Fluid-derived EV in patients with the healing chronic wound is rich in miR-21 and results in more efficient cell conversion than in the fluid of non-healing subjects. It is reported that failed conversion in diabetic wound tissue is improved by nanoparticles-mediate delivery of targeted miR-21 to macrophages [89].
Another miRNA that has a significant role in diabetes is miR-126. miR-126 is considered a DM biomarker, and its loss carries a risk of abnormal angiogenesis, vascular leakage, and peripheral artery disease [90,91,92,93]. miR-126-5p can impede the progression of cervical cancer the human through the regulation of the cancer cell apoptosis directly by targeting Bcl-2 [94]. The secretion of miR-126 is declined in human diabetic failing heart tissues when compared with non-diabetic normal heart tissues, which led us to investigate the miR-126 performance in diabetic efferocytosis so that miR-126 overexpression in macrophages applying mimics decreased expression of ADAM9 [95]. Moreover, the luciferase assay’s target validation highlighted the ADAM9 as a direct target of miR-126 in macrophages [95]. Otherwise, when ADAM9 is inhibited, MerTK protein remains uncut, and subsequently, efferocytosis increases (Fig. 5). The secretion of ADAM9 is elevated in exposure to a great glucose level, which is reversed via miR126 mimic transfection in macrophages under HG conditions. The HG treatment in macrophages can elevate the level of a soluble MerTK (sMer).
The MerTK protein can be interestingly cleaved by the ADAMs in exposure to a great glucose level; thus, it will be inactivated [95]. The ADAM family of metalloproteases are cellular mediators, with the first known role in gamete fusion, which suggests their adhesion properties in intercellular interactions and involvement in tumor biology. The ADAM proteins are vital factors in regulating neoplastic procedures because of their impact on cell migration, adhesion, cell signaling, and proteolysis [93]. The ADAM17 breaks transmembrane MerTK, and generates the sMer [39]. The soluble MerTK inactivates the protein and prevents macrophage removal of apoptotic cells, thrombosis, and platelet aggregation in mice [39, 96]. Based on documents, the MerTK causes pyrenocyte engulfment via fundamental macrophages in erythroblastic islands and enhances the acute lymphoblastic leukemia survival in central nervous system, as the signals of ‘eat me or ‘eat me not’ [97, 98]. Macrophages are the main source of MerTK secretion and thus progress efferocytosis and impede inflammation [99, 100].
Conclusions
An integral part of cell circulation in various organs is apoptosis. If the dead cells are not cleaned enough, and their contents are not released, the tissue is damaged, and prolonged inflammation occurs. It is clear that defective phagocytosis of dead cells in the pancreas leads to the onset and progression of chronic diabetic inflammation. In recent years, information on the pathways implicated in efferocytosis and potent pharmacological targets has been significantly enhanced, increasing the clearance efficiency of apoptosis. Because reduced phagocytosis is associated with an increase in inflammation, targeting efferocytosis to increase dead cell clearance may contribute to diabetic wound healing.
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Mahmoudi, A., firouzjaei, A.A., darijani, F. et al. Effect of diabetes on efferocytosis process. Mol Biol Rep 49, 10849–10863 (2022). https://doi.org/10.1007/s11033-022-07725-2
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DOI: https://doi.org/10.1007/s11033-022-07725-2