Neutrophil sub-types in maintaining immune homeostasis during steady state, infections and sterile inflammation.

INTRODUCTION: Neutrophils are component of innate immune system and a) eliminate pathogens b) maintain immune homeostasis by regulating other immune cells and c) contribute to the resolution of inflammation. Neutrophil mediated inflammation has been described in pathogenesis of various diseases. This indicates neutrophils do not represent homogeneous population but perform multiple functions through confined subsets. Hence, in the present review we summarize various studies describing the heterogeneous nature of neutrophils and associated functions during steady state and pathological conditions. METHODOLOGY: We performed extensive literature review with key words 'Neutrophil subpopulations' 'Neutrophil subsets', Neutrophil and infections', 'Neutrophil and metabolic disorders', 'Neutrophil heterogeneity' in PUBMED. RESULTS: Neutrophil subtypes are characterized based on buoyancy, cell surface markers, localization and maturity. Recent advances in high throughput technologies indicate the existence of functionally diverse subsets of neutrophils in bone marrow, blood and tissues in both steady state and pathological conditions. Further, we found proportions of these subsets significantly vary in pathological conditions. Interestingly, stimulus specific activation of signalling pathways in neutrophils have been demonstrated. CONCLUSION: Neutrophil sub-populations differ among diseases and hence, mechanisms regulating formation, sustenance, proportions and functions of these sub-types vary between physiological and pathological conditions. Hence, mechanistic insights of neutrophil subsets in disease specific manner may facilitate development of neutrophil-targeted therapies.

Neutrophil (dys)function due to altered immuno-metabolic axis in type 2 diabetes: implications in combating infections.

Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory 'feed forward loop'. Nutrient 'excess' conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and ß-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.

Ethnic disparities attributed to the manifestation in and response to type 2 diabetes: insights from metabolomics.

Type 2 diabetes (T2D) associated health disparities among different ethnicities have long been known. Ethnic variations also exist in T2D related comorbidities including insulin resistance, vascular complications and drug response. Genetic heterogeneity, dietary patterns, nutrient metabolism and gut microbiome composition attribute to ethnic disparities in both manifestation and progression of T2D. These factors differentially regulate the rate of metabolism and metabolic health. Metabolomics studies have indicated significant differences in carbohydrate, lipid and amino acid metabolism among ethnicities. Interestingly, genetic variations regulating lipid and amino acid metabolism might also contribute to inter-ethnic differences in T2D. Comprehensive and comparative metabolomics analysis between ethnicities might help to design personalized dietary regimen and newer therapeutic strategies. In the present review, we explore population based metabolomics data to identify inter-ethnic differences in metabolites and discuss how (a) genetic variations, (b) dietary patterns and (c) microbiome composition may attribute for such differences in T2D.