**6. Dysfunctional macrophages**

Early host defence against intracellular bacterial infections is greatly aided by macrophages. In order to control infection, macrophages perform crucial effector tasks such as phagocytosing pathogens and eliminating necrotic and apoptotic neutrophils. Activation and recruitment of circulating monocytes to infection sites, where they undergo macrophage differentiation, are aided by cytokines and chemokines produced by neutrophils, such as TNF- and CCL2 [37]. The macrophage cytokine profile is essential for promoting efficient cell-mediated immunity and defence against intracellular bacteria in addition to phagocytic and antibacterial processes. Inducible nitric oxide synthase, co-stimulatory molecules, and inflammatory cytokines like TNF-, IL-12, and IL-18 are all up-regulated as a result of M1 macrophage polarisation in response to intracellular bacterial infections. IFN- production from NK cells depends on the production of IL-12 and IL-18 [38]. Inducible nitric oxide synthase, co-stimulatory molecules, and inflammatory cytokines like TNF-, IL-12, and IL-18 are all up-regulated as a result of M1 macrophage polarisation in response to intracellular bacterial infections. In order to create T helper type 1 (Th1) cell-mediated immunity, NK cells and T cells must produce IL-12 and IL-18 in order to trigger an IFN- response [37]. Both IFN and TNF stimulate inducible nitric oxide synthase and NADPH oxidase, which activate macrophages and aid in the destruction of intracellular microorganisms.

The way that macrophages work is also changed by hyperglycemia. Chronic hyperglycemia gets significantly correlated with deficiencies in complement receptors and Fc receptors on isolated monocytes, impairing phagocytosis [39]. Reduced phagocytosis and antibacterial activity were seen in an in vitro experiment utilising macrophages generated from mice bone marrow and treated with high glucose. Reduced phagocytosis was seen in peritoneal macrophages from diabetic mice in the same investigation [39]. This might be connected to macrophages' decreased glycolytic reserve and capacity as a result of their long-term sensitivity to high glucose levels.

Phagocytosis and adhesion capacity in RPMs of db/db mice decreases significantly thereby employing resident peritoneal macrophages (RPMs) obtained from mice. Additionally, compared to control mice, db/db mice showed enhanced macrophage polarisation shifting to M2 macrophages. A similar rise in M2 macrophage markers, such as Arginase 1 and IL-10, was observed in macrophages generated from mice bone marrow and exposed to high glucose for an extended length of time [40]. The immune response to bacterial infection may be weakened by this shifting since M2 macrophages have a low potential for microbicidal activity.

## **7. Ineffective natural killer cells**

Innate immune responses to pathogens are mostly mediated by natural killer cells, and during the past 10 years, research into the protective effects of these cells against intracellular bacterial infections has acquired significant impetus. Numerous inhibitory and activating receptors control natural killer cells. Isolated NK cells from T2D patients were used to demonstrate the dysfunction of natural killer (NK) cells, which are crucial for containing invasive pathogens [41]. It was discovered that defects in the NK cell-activating receptors NKG2D and NKp46 were linked to functional defects in NK degranulation capacity [42].

NK cells with T-cell receptors are a special subset known as natural killer T (NKT) cells. They have the capacity to enhance a variety of immune responses and react to glycolipid antigens rather than peptide antigens. There is proof that NKT cells aid in host defence during *M. tuberculosis* infection by suppressing intracellular bacterial growth through cytolytic processes, promoting antigen-presenting cell (APC) maturation and activation, and modifying the sort of immune response elicited [43]. In experimental models of diabetes, the role of NKT cells in adipose tissue inflammation and glucose intolerance has been discussed. Increases in NKT cell numbers are seen in tuberculosis patients, and those with co-morbid diabetes had higher levels of NKT cells in their blood and bronchoalveolar lavage than those without TB [44]. This has been proposed as a helpful marker for active tuberculosis and may be a direct result of the elevated bacillary burden seen in these patients.

#### **7.1 Impaired immune and complement system**

In a study on rats the malfunction of complement activation was noted. They showed that elevated blood sugar levels were linked to a reduction in C4-fragment opsonization, which blocks the classical or lectin pathways of complement activation [44]. **Table 1** provides an overview of the potential pathways that lead to infection susceptibility in diabetics.

The results described in the previous section imply that islet macrophages have protective effects and help to maintain islet homeostasis. However, recent studies have also demonstrated that they play a significant role in the islet pathology in T2D [63]. The number of macrophages within islets was found to be increased in pancreas sections from T2D patients, C57BL/6 mice given a high-fat diet, db/db mice, and Goto-Kakizaki (GK) rats by immunohistochemical analysis [64]. Additionally, it has been claimed that high glucose or palmitate caused the production of chemokines from the islets, which aided in monocyte and neutrophil migration. This shows that the type 2 diabetic environment may encourage macrophage infiltration into pancreatic islets and stimulate chemokine production [65].

The build-up of macrophages within T2D islets points to their pathological function. It has been noted that macrophages perform seemingly incompatible tasks in islets as well as in other organs and conditions. In reality, recent research has shown that macrophages are actually extremely diverse [66]. According to in vitro research, Th1 cytokines alone or in combination with microbial products cause macrophages to activate in the traditional M1 manner, whereas Th2 cytokines (IL-4 and IL-13) cause an alternative type of activation known as M2 [53]. ActivatedM2-type macrophages enhance wound healing and may also modify immunological responses, whereas classically activatedM1 type macrophages play a key role in host defence by secreting proinflammatory cytokines and ROS. However, the phrase "M2 activation" is somewhat amorphous and is used to refer to a variety of M1-independent macrophage activation mechanisms [54].

M2 macrophages may therefore act differently depending on the environment. The functions of various macrophage subsets in the onset and development of disease, as well as their potential contributions to the preservation of homeostasis, are now well understood. Because macrophages have a variety of activation phenotypes, we examined the polarity of macrophage activation inside islets. We identified two distinct subpopulations of islets using flow cytometry: CD11b+Ly-6C+CD11b+F4/80+Ly-6C-T2D and CD11b+Ly-6C+CD11b+Ly-6C. healthier islet. CD11bhighF4/80−/+Ly-6C+ Diabetes type 2 and islet macrophage polarity (T2D). Healthy islets have a high percentage of resident macrophages that display CD11b+F4/80+Ly-6C [67].


*Perspective Chapter: Immunosuppression in Patients with Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.107362*


#### **Table 1.**

*The immunological mechanism underlying infection susceptibility in diabetics.*

Monocytes/macrophages and CD11b+Ly-6Cmacrophages accumulate in T2D islets. T2D islet CD11b high F4/80+Ly 6C+monocytes/macrophages are also present. Islet-resident macrophages were predominately CD11b+Ly-6C cells with an M2-type phenotype under baseline circumstances. In comparison to control db/+ and KKTa animals, fractions of these M2-type cells were not altered in db/db or KKAy model T2D mice, respectively [55]. On the other hand, the T2D models had a specifically higher number of CD11b+Ly-6C+macrophages. These cells have an M1-type phenotype and express pro-inflammatory cytokines like IL-1 and TNF. As a result, in T2D islets, macrophage polarity seems to have switched toward M1 [56].

Inflammasome activation and High Glucose in T2D Islets. The polarity of macrophages within T2D islets is altered toward M1. Recent research has uncovered a number of mechanisms, including immune cell recruitment and the elevation of inflammatory cytokines (such IL-1), that underlie the activation of inflammatory processes within islets [57]. For instance, as was already established, the environment of type 2 diabetes may stimulate the creation of chemokines that encourage macrophage infiltration into pancreatic islets. Multiprotein complexes called inflammasomes are crucial for the development and release of IL-1. Two stimuli are necessary to initiate IL-1 secretion: the first stimulates pro-IL-1 protein expression, and the second activates inflammasomes, which in turn activate caspase I to cleave pro-IL-1 and produce mature IL-1 [58].

#### *Perspective Chapter: Immunosuppression in Patients with Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.107362*

According to a recent study, minimally modified LDL, which triggers TLR4 signalling in macrophages and primes them to process Il-1, is one of the initial stimuli in T2D islets. The second stimulus was determined to be islet amyloid polypeptide (IAPP), a distinct polypeptide component of amyloid present in pancreatic islets and which is produced from cells in response to high glucose. IAPP, a soluble oligomer, activates the NLRP3 inflammasome and causes the islet macrophages to secrete IL-1 [59]. As a result, the interaction between macrophages and -cells is crucial for inflammasome activation within islets. Additionally, it has been demonstrated that high glucose-induced ROS production in cells causes the activation of the NLRP3 inflammasome and the release of IL-1 [60].

Islet inflammation leads to Cell dysfunction in T2D. Despite the fact that it seems as though high glucose levels are a necessary trigger for islet inflammation, a recent examination of -cell function revealed that impaired glucose tolerance was already present before glucose-induced insulin secretion deteriorated. This shows that cell dysfunction can start and progress in response to triggers other than excessive glucose levels [45]. FFAs are a potential contender for such stimulation. Clinical studies have shown that FFA levels are a reliable predictor of future T2D and a high consumption of saturated fatty acids has been associated with an increased risk of T2D. The most prevalent saturated FFA in blood is palmitate, and studies have shown that it has harmful effects on -cells that are collectively known as "lipotoxicity" [46].

Studies conducted in vitro have demonstrated that palmitate directly induces -cell lipotoxicity, at least in part through mechanisms predominantly involving ER stress and ROS. We created a technique to elevate non-esterified palmitate levels in the serum by injecting emulsified ethyl palmitate in order to assess the effects of palmitate on -cells in vivo. This model demonstrated that palmitate activates TLR4 to generate chemokines, such as CCL2 and CXC11, in cells [47]. These chemokines caused CD11b+Ly-6C+M1-type monocytes and macrophages to be attracted to the islets. Additionally, palmitate-induced -cell dysfunction was decreased when M1-type cells were prevented from accumulating by utilisingclodronate liposomes, demonstrating their causative involvement [48].

Additionally, it was discovered that M1 macrophages' production of proinflammatory cytokines, such as IL-1 and TNF-, encourages -cell dysfunction and that the vicious loop created by the secretion of chemokines by -cells and cytokines by M1 macrophages speeds up islet inflammation [49]. Similar to this, M1 macrophage increase within islets in T2D models (db/db and KKAy animals) appears to lead to cell dysfunction. These findings unequivocally demonstrate that inflammation-related islet dysfunction comes from the stimulation of inflammatory mechanisms [68].

Inflammation as a Pharmacological Target for T2D: Due to the role that IL-1 plays in the emergence of T2D and -cell dysfunction, therapeutic approaches that target the IL-1 receptor and IL-1 ligand have been developed. Rheumatoid arthritis is treated with recombinant human IL-1RA (anakinra), a medication that blocks IL-1 receptor signalling [69]. IL-1RA presumably inhibits both IL-1 and IL-1 signalling since it suppresses the IL-1 receptor. Anakinra was tested in a clinical trial to see if it could improve -cell function and glycaemic control in T2D patients. The anakinra group demonstrated improved HbA1c levels and serum C-peptide concentrations during oral glucose tolerance test (OGTT) with no significant differences in insulin sensitivity, indicating that improved cell function played the major role in the improvement in glucose tolerance [70].

A follow-up investigation showed that the decreased proinsulin-to-insulin ratio persisted for 39 weeks after the end of the treatment. In GK rats and mice fed a highfat diet, the processes underlying these observations were further examined. IL-1RA enhanced insulin sensitivity and beta-cell activity in these animals by suppressing inflammation in insulin target tissues and islets. There was a noticeable decrease in islet macrophage counts in GK rats treated with IL-1RA, indicating that islet macrophages may be one of the targets of the anakinra treatment [71]. Finally, despite the drug improving the glucose disposition index during OGTT, no appreciable change in insulin sensitivity or -cell function was seen in a recent investigation assessing the effects of anakinra on obese adult individuals without T2D.

Additionally, IL-1-specific antibodies have been created. The therapeutic effects of gevok-izumab, a recombinant humanised monoclonal antibody that neutralises IL-1, were examined in T2D participants. The fact that this medication preserves IL-1 signalling and has a longer half-life (22–25 days), which lowers the frequency of administration and lowers the cost, may make it superior to anakinra [50]. Gevokizumab significantly decreased HbA1c, C-peptide secretion, and CRP at a low dose (0.3 mg/ kg), but not at a high dose (0.03–0.1 mg/kg). The discovery that a large dose failed to exhibit positive effects may support the idea that IL-1 at low concentrations is advantageous for cells [51]. The scientists came to the conclusion that the right dosage and duration of gevokizumab therapy are essential for changing the immune system in T2D patients. Salsalate, a salicylic acid prodrug having inhibitory effects on the NF-B pathway, and TNF-inhibitors have both been investigated in T2D [72].

These research' encouraging findings are in line with the idea that T2D can be treated by reducing the inflammation induced by diabetes.

### **8. Future perspective**

A serious global concern is the dual burden of intracellular bacterial infections and diabetes. The majority of current diagnostic and therapeutic research involves non-diabetic mice, and it is unclear whether these findings can be applied to people with diabetes given the obvious disparities in immune responses and disease mechanisms. There is considerable clinical and experimental evidence that a delay in innate immune system inflammatory signals is followed by delayed development of effective protective responses against intracellular bacterial infections, notwithstanding the complexity of the underlying immunopathology of diabetes. It is likely that a more multifaceted therapeutic approach will be required to address the complicated immunopathogenesis underlying diabetes, even while better glucose management may assist patients with intracellular infections and co-morbid diabetes. It will be easier to treat and manage disease in sensitive populations if we are aware of the mechanisms driving co-morbidities like diabetes, which profoundly affect the development of intracellular bacterial infections. Innovative, cost-effective strategies are desperately needed, especially in low- and middle-income nations where there has never been a greater convergence of non-communicable and communicable diseases. A multidisciplinary approach with an extensive study is required to tackle the present and future issues of the rising double burden of co-morbid intracellular bacterial infections leading to continued and widespread existence of non-communicable illnesses.

## **9. Conclusion**

Diabetes is a metabolic disorder brought on by inflammation in an advanced immune system. Insulin resistance results in a multitude of immunological reactions
