CD14+ monocytes are vulnerable and functionally impaired under endoplasmic reticulum stress in patients with type 2 diabetes.
OBJECTIVE
Although patients with diabetes suffer from increased infections and a higher incidence of cancer due to impaired immune function, details on diabetes-induced decrease in immunity are lacking. We assessed how immune-mediating peripheral blood mononuclear cells (PBMCs) are affected in diabetes.


METHODS
From 33 patients with type 2 diabetes and 28 healthy volunteers, we obtained PBMCs and investigated their susceptibility to apoptosis and functional alteration.


RESULTS
In a subpopulation of PBMCs, monocytes derived from patients with diabetes were more susceptible to apoptosis than monocytes from healthy volunteers. Monocytes from patients with diabetes had decreased phagocytotic activity and were less responsive to Toll-like receptor (TLR) ligands, although the expression of TLRs did not differ significantly between the two groups. Furthermore, monocytes from patients with diabetes had a distinctly different gene expression profile compared with monocytes from normal volunteers as assessed with DNA microarray analysis. Specifically, quantitative real-time detection PCR measurements showed an elevated expression of the markers of endoplasmic reticulum (ER) stress in diabetic monocytes, and electron microscopic examination of monocytes revealed morphologic alterations in the ER of cells derived from patients with diabetes. Consistently, the ER stress inducer tunicamycin increased apoptosis of otherwise healthy monocytes and attenuated the proinflammatory responses to TLR ligands.


CONCLUSIONS
These data suggest that monocytes comprise a substantially impaired subpopulation of PBMCs in patients with diabetes and that ER stress is involved in these pathologic changes mechanistically. This implies that the affected monocytes should be investigated further to better understand diabetic immunity.
Komura
Takuya
T
Disease Control and Homeostasis, Kanazawa University, Graduate School of Medical Science, Kanazawa, Japan.
Sakai
Yoshio
Y
Honda
Masao
M
Takamura
Toshinari
T
Matsushima
Kouji
K
Kaneko
Shuichi
S
D000368:Aged; D017209:Apoptosis / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000473:pathology*; D004198:Disease Susceptibility / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D020411:Oligonucleotide Array Sequence Analysis; D010587:Phagocytosis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013312:Stress, Physiological / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018950:Lipopolysaccharide Receptors; D051193:Toll-Like Receptors