Abstract
Initiation of type 1 diabetes (T1D) is marked by the infiltration of plasmacytoid dendritic cells (pDCs) and monocytes in pancreatic islets. Dying beta cells release self-DNA, which forms complexes with antimicrobial peptide, LL37, and its delayed clearance can activate pDCs and monocytes. Here, we studied the phenotypic effects of DNA-LL37 complexes on pDCs and monocytes in 55 recently diagnosed T1D and 25 healthy control (HC) subjects. Following in vitro stimulation with DNA-LL37 complexes, T1D group demonstrated higher frequency and mean fluorescence intensity (MFI) of pDCs expressing IFN-α. Similarly, the monocytes in T1D group showed an increase in MFI of IFN-α. Post-stimulation, an increase in the antigen presentation and co-stimulatory ability of pDCs and monocytes was observed in T1D group, as indicated by higher expression of HLA-DR, CD80 and CD86. Upon co-culture, the stimulated monocytes and pDCs, particularly in the T1D group were able to further activate autologous CD4 + T cells, with increase in expression of CD69 and CD71. Finally, in a transwell assay, the stimulated pDCs and monocytes induced an increase in apoptosis of 1.1B4 beta cells. Additionally, we observed reduced expression of indoleamine 2,3-dioxygenase 1 (IDO1) in pDCs and monocytes of T1D subjects. Our results suggest that DNA-LL37 complexes activate pDCs and monocytes towards a proinflammatory phenotype during pathogenesis of T1D.
Highlights
Initiation of type 1 diabetes (T1D) is marked by the infiltration of plasmacytoid dendritic cells and monocytes in pancreatic islets
Evidence of the role of self-DNA can be further deduced from the fact that circulating DNA from beta cells has been detected in recent-onset T1D subjects[21], along with increased neutrophilic activity, which may lead to the formation of DNA-immune complexes in the islets as suggested by Diana et al 20139
Our findings revealed a pathway by which self-DNA triggers IFN-α response upon binding with LL37 antimicrobial peptide indicating the possible role of DNA-LL37 complexes in creating beta cell-specific autoimmune responses via plasmacytoid dendritic cells (pDCs) and monocytes
Summary
Initiation of type 1 diabetes (T1D) is marked by the infiltration of plasmacytoid dendritic cells (pDCs) and monocytes in pancreatic islets. Dying beta cells release self-DNA, which forms complexes with antimicrobial peptide, LL37, and its delayed clearance can activate pDCs and monocytes. Whether LL37 aided transport of self-DNA into monocytes and pDCs can lead to activation of these cells and increased type I IFN in subjects with T1D, is still unknown. We investigated whether the uptake of DNA-LL37 complexes confers a proinflammatory phenotype to pDCs and monocytes by either increasing IFN-α production or enhancing their antigen presentation capacity in terms of increased expression of HLA-DR, CD80 and CD86. Our study revealed a mechanism whereby self-DNA upon binding with LL37 triggers an IFN-α response leading to activation of pDCs and monocytes, which further activate CD4 + T cells and cause beta cell apoptosis
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