Abstract
Increased formation of neutrophil extracellular traps (NETs) is associated with gut leakage in type 1 diabetes (T1D). To explore the mechanism of how enteropathy exacerbated by NETs triggers pancreatic autoimmunity in T1D, we carried out a correlation analysis for NET formation with gut barrier functions and autoimmunity in nonobese diabetic (NOD) mice. Inducing chronic colitis or knocking out of peptidyl arginine deiminase type 4 (PAD4) in NOD mice were used to further study the effect of NET formation on the progression of T1D. Microbial alterations in Deferribacteres and Proteobacteria, along with the loss of gut barrier function, were found to be associated with increased endotoxin and abnormal formation of NETs in NOD mice. Both DSS-induced colitis and knockout of PAD4 in NOD mice indicated that PAD4-dependent NET formation was involved in the aggravation of gut barrier dysfunction, the production of autoantibodies, and the activation of enteric autoimmune T cells, which then migrated to pancreatic lymph nodes (PLNs) and caused self-damage. The current study thus provides evidence that PAD4-dependent NET formation is engaged in leaky gut triggering pancreatic autoimmunity and suggests that either degradation of NETs or inhibition of NET formation may be helpful for innovative therapeutic interventions in T1D.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic beta cells destroyed by autoreactive T cells [1, 2]
We recently reported that degradation of neutrophil extracellular traps (NETs) in the gut of nonobese diabetic (NOD) mice by nuclease production due to recombinant Lactococcus lactis could protect against T1D development [22]
The strong correlation between LPS and H3cit only in NOD mice (Figure 1F) but not BALB/c mice (Figure 1G) suggested that the loss of gut barrier function and the invasion of booming gramnegative bacteria led to the abnormal generation of NETs before T1D onset, which could be a potential pathogenic factor
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by insulin-producing pancreatic beta cells destroyed by autoreactive T cells [1, 2]. Neutrophil Extracellular Traps in NOD components, followed by the generation of islet-reactive CD4- or CD8-positive T cells [7] in gut-associated lymphoid tissue (GALT), and these cells possess PLN homing abilities and induce insulitis [8,9,10]. In this process, the transition from innate immunity to adaptive immunity after losing gut barrier integrity has rarely been mentioned. B cells activated by self-DNA produce an anti-dsDNA antibody to trigger an autoimmune response [21]
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