SUMMARY Neutrophils were long considered to be a short-lived homogenous cell population, limited to their role as first responders in anti-bacterial and -fungal immunity. While it is true that neutrophils are first to infiltrate the site of infection to eliminate pathogens, growing evidence suggests their functions could extend beyond those of basic innate immune cells. Along with their well-established role in pathogen elimination, utilizing effector functions such as phagocytosis, degranulation and the deployment of neutrophil extracellular traps (NETs), neutrophils have recently been shown to possess antigen-presenting capabilities. Moreover, the identification of different subtypes of neutrophils points to a multifactorial heterogeneous cell population with great plasticity in which some subsets have enhanced pro-inflammatory characteristics, while others seem to behave as immunosuppressors. Interestingly, the aberrant presence of activated neutrophils with a pro-inflammatory profile in several systemic and organ-specific autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), multiple sclerosis (MS), and type 1 diabetes (T1D) could potentially be exploited in novel therapeutic strategies. The full extent of the involvement of neutrophils, and more specifically that of their various subtypes, in the pathophysiology of autoimmune diseases is yet to be elucidated.
Background and aims: Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by a T-cell-mediated destruction of the pancreatic insulin-producing beta cells. A growing body of evidence suggests that abnormalities in neutrophils and neutrophil extracellular trap (NET) formation (NETosis) are associated with T1D pathophysiology. However, little information is available on whether these changes are primary neutrophil defects or related to the environmental signals encountered during active disease. Methods: In the present work, the NET proteome (NETome) of phorbol 12-myristate 13-acetate (PMA)- and ionomycin-stimulated neutrophils from people with established T1D compared to healthy controls (HC) was studied by proteomic analysis. Results: Levels of NETosis, in addition to plasma levels of pro-inflammatory cytokines and NET markers, were comparable between T1D and HC subjects. However, the T1D NETome was distinct from that of HC in response to both stimuli. Quantitative analysis revealed that the T1D NETome was enriched in proteins belonging to metabolic pathways (i.e., phosphoglycerate kinase, glyceraldehyde-3-phosphate dehydrogenase, and UTP-glucose-1-phosphate uridylyltransferase). Complementary metabolic profiling revealed that the rate of extracellular acidification, an approximate measure for glycolysis, and mitochondrial respiration were similar between T1D and HC neutrophils in response to both stimuli. Conclusion: The NETome of people with established T1D was enriched in metabolic proteins without an apparent alteration in the bio-energetic profile or dysregulated NETosis. This may reflect an adaptation mechanism employed by activated T1D neutrophils to avoid impaired glycolysis and consequently excessive or suboptimal NETosis, pivotal in innate immune defence and the resolution of inflammation.
<p>Immunomodulation combined with antigen therapy holds great promise to arrest autoimmune type 1 diabetes, but clinical translation is hampered by a lack of prognostic biomarkers. Low-dose anti-CD3 plus <em>Lactococcus lactis </em>(<em>L. lactis</em>) bacteria secreting proinsulin and IL-10 reversed new-onset disease in non-obese diabetic (NOD) mice, yet some mice were resistant to the therapy. Using microRNA (miRNA) profiling, six miRNAs (i.e., miR-34a-5p, miR-125a-3p, miR-193b-3p, miR-328, miR-365-3p, and miR-671-3p) were identified as differentially expressed in plasma of responder versus non-responder mice before study entry. After validation and stratification in an independent cohort, plasma miR-193b-3p and miR-365-3p combined with age and glycemic status at study entry had the best power to predict with high sensitivity and specificity poor response to the therapy. These miRNAs were highly abundant in pancreas infiltrating neutrophils and basophils with a pro-inflammatory and activated phenotype. Here, a set of miRNAs and disease-associated parameters are presented as predictive signature for the <em>L. lactis</em>-based immunotherapy outcome in new-onset type 1 diabetes, hence allowing targeted recruitment of future trial participants and accelerated trial execution. </p>
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