## 3 Discussion
In addition, the function of antigen recognition by the CD163+ monocyte was decreased in individuals with diabetes and complications compared to those without, although a very low proportion of TLR4+ cells was detected in the CD163+ cells from both groups. The down-regulated _TLR4_ would be consistent with a diminished capacity of the CD163+ monocytes to recognize and internalize antigens such as pathogen-associated molecular pattern molecules (PAMPs) and damage associated molecular pattern molecules (DAMPS), leading to an inadequate immune response, impaired pathogen clearance [17], and continued inflammation (Figure 6). The down-regulated _TLR4_ in CD163+ cells, which are a 'hub-node', raises the proposition that the reduced TLR4 functionality would trigger a cascade of events involving both monocyte function and immune response, thereby contributing to the development of complications [18]. Contrastingly, an earlier study in a rat model of retinopathy in diabetes reported that increased TLR4 in retinal extracts was associated with disease progression [19] and that the blockade of the TLR4 signaling pathway reduced inflammation [19; 20; 21], thus indicating that the TLR4 signaling must be tightly regulated to prevent excessive inflammation. The ability of the CD163+ monocytes to clear and regulate extracellular ATP may be potentially diminished in individuals with diabetes complications due to the decreased expression of the ectonucleotides CD39 and CD73 (Figure 6). Dysregulation of extracellular ATP may impair the supply and formation of adenosine, an anti-inflammatory mediator, which would lead to a pro-inflammatory environment [22]. Similarly, a recent study found the lowest CD39 expression in circulating lymphocytes in individuals with diabetes-related complications, compared to those without [23]. Decreased CD39 expression has also been  
Figure 6: An infographic depicting the RNA and protein level functional alterations in the CD163+ monocytes of individuals with diabetes-related complications. The first panel describes mechanisms of increased apoptosis, the second panel depicts mechanisms involved in reduced trans-endothelial migration, the third panel depicts reduced CD163+ monocyte function, whilst the fourth panel depicts monocyte interactions. implicated in reduced monocyte-mediated lymphocyte activation [24]. This suggests that the unresolving nature of diabetes-related complications may be due to the dysregulated interaction between the antigen-presenting CD163+ monocytes and the adaptive immune system (Figure 6). We observed an increased expression of the gene _CD5_ in CD163+ monocytes in individuals with diabetes-related complications. _CD5_ has been reported to suppress the activation of peripheral T cells through the inhibition of T cell receptors at the immunological synapse [25]. Similarly, CD86, a co-stimulatory molecule necessary for effective T cell activation and survival [26] was also down-regulated in the CD163+ monocytes in D\({}^{+\text{Comps}}\). As summarized in Figure 6, our results suggest that CD163+ monocyte-mediated T cell activation was down-regulated in individuals with diabetes-related complications, due to the increased _CD5_ and decreased CD86 expression. However, we also propose an alternative pathway for T cell activation involving the up-regulated expressions of _CD7_ and _ZAP-70_, which are both implicated in the initiation of T cell responses via the antigen receptor [27, 28]. This may indicate a possible connection point between the non-specific immune response driven by monocytes and the adaptive and specific immune response mediated by T cells. Furthermore, in diabetes-related complications, CD163+ monocyte-mediated immunosuppression was potentially reduced due to the decreased expression of the immune inhibitory receptor _CD200R1_ (Figure 6). The interaction of _CD200_ with its receptor _CD200R1_ typically evokes an immunosuppressive response [29].