Increased Toll-Like Receptor (TLR) 2 and TLR4 Expression in Monocytes from Patients with Type 1 Diabetes: Further Evidence of a Proinflammatory State

Abstract

Thus, we make the novel observation that TLR2 and TLR4 expression and signaling are increased in T1DM and contribute to the proinflammatory state.

TLR2 expression and signaling-dependent inflammation impair wound healing in diabetic mice

“…Previously, we have shown that diabetic patients have increased monocytic TLR2 and TLR4 expression, which correlated to increased NF-kB activity, increased expression of downstream adapter proteins such as MyD88 and pIRAK, resulting in increased pro-inflammatory cytokines. 28 Similar findings were found when cells were treated in vitro under hyperglycemic conditions. 26 Thus, we suggest that abrogating inflammation in diabetic wounds using TLR2 as a target appears to be a reasonable approach to alleviate inflammation accelerating diabetic wound-healing process.…”

“…Although TLR2 has been shown to be upregulated in NOD mice 30 and T1DM patients, 28 its role in contributing to the exacerbated inflammatory state of diabetic wounds is unclear. Furthermore, increasing experimental evidence indicates that engagement of the TLR2 by endogenous ligands may be a major trigger of inflammation in response to skin injury, ischemia, hemorrhagic shock, and ischemia/reperfusion injuries.…”

“…Further analysis of adjacent normal skin (TLR2: 2.2 ± 0.4; TLR6: 2.1 ± 0.4 mRNA/ 18s ratio) and diabetic wounds (TLR2: 2.7 ± 0.4; TLR6: 2.6 ± 0.3 mRNA/18s ratio) in mice revealed no significant differences in mRNA expression implying that alterations in TLR2/6 expression may be because of hyperglycemia principal to diabetes, as shown earlier. 26,28 Because we did not observe significant difference in biochemical parameters, wound closure (Figure 2a), and TLR2/6 mRNA expression in wounds of nondiabetic C57BL/6J and TLR2 À/À mice, we focused our molecular analyses on wounds of diabetic mice. Recently, we have shown that TLR2 and TLR6 heterodimerization results in the recruitment of MyD88 and activation of the downstream signaling pathway through phosphorylation of IRAK-1, activation of TRIF, NF-kB, and upregulated expression of proinflammatory cytokines under hyperglycemia.…”

Danger, intracellular signaling, and the orchestration of dendritic cell function in skin sensitization

“…The MyD88 dependent signaling pathway activates both NF-κB and the mitogen-activated protein kinases (MAPK). Ultimately, activation of these molecules leads to an increase in the transcription of the pro-inflammatory cytokines TNFα and pro-IL-1β amongst others (Devaraj et al, 2008). As discussed previously, these pro-inflammatory cytokines are important components in contact allergen-dependent activation of DC and, thus, activation of NF-κB and MAPK might therefore be important in contact allergen-dependent activation of DC.…”

Auditing Protein Therapeutics Management by Professional APCs: Toward Prevention of Immune Responses against Therapeutic Proteins

“…The type 1 diabetes patients also showed significant augmentation of downstream elements of TLR signaling and release of the proinflammatory cytokines IL-1 ␤ and TNF-␣ when compared with the control population. The release of proinflammatory cytokines strongly correlated with the increased expression of TLRs in the patient population that in turn strongly correlated with pathological signs like hemoglobin glycosylation (28). Proinflammatory cytokines like GM-CSF have been shown to augment MHCII and costimulatory molecules like CD86 and CD40 on monocytes (29).…”