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

Abstract

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.

Keywords: Auto immune diseases; Granulopoiesis; Heterogeneity; Infections; Neutrophils.

Fig. 1

Life cycle of neutrophils in steady state. HSCs through series of differentiation forms promyelocyte, myelocyte, metamyelocyte, band cell and finally mature neutrophil. Steady increase in CXCR2 level and decrease in CXCR4 expression leads to release of neutrophils from the bone marrow to circulation. From circulation, neutrophils enter into various tissues majorly into lungs, liver and spleen. As neutrophils age, increase in the expression of CXCR4, migrates back into bone marrow for clearance by resident stromal macrophages. Neutrophils are also cleared in liver and spleen

Fig. 2

Low density neutrophils in diseases. Based on density neutrophils are characterized into low density neutrophils (LDNs) and normal density neutrophils (NDNs). LDNs are found in both normal physiology and pathological conditions. LDNs with surface marker CD33 CD66 CD11b CD15 found in several diseases such as HIV-1, cancer, diabetes and systemic lupus erythematosus which suppresses T cells and NK cells

Fig. 3

Paradoxical role of neutrophils in tumors. In tumor microenvironment, Anti-tumor N1 TANs display cytotoxicity, immune memory, rejection of tumour, producing lower arginase. Whereas pro-tumor N2 TANs gets involve in invasion, metastasis, immune suppression and angiogenesis leading to the progression of tumor

Fig. 4

Neutrophil subsets in physiological and pathological states. The illustration shows various neutrophil subtypes characterized by differential expression of surface markers identified in steady state and diseases