The Neutrophil: Constant Defender and First Responder

Abstract

The role of polymorphonuclear neutrophils (PMNs) in biology is often recognized during pathogenesis associated with PMN hyper-or hypo-functionality in various disease states. However, in the vast majority of cases, PMNs contribute to resilience and tissue homeostasis, with continuous PMN-mediated actions required for the maintenance of health, particularly in mucosal tissues. PMNs are extraordinarily well-adapted to respond to and diminish the damaging effects of a vast repertoire of infectious agents and injurious processes that are encountered throughout life. The commensal biofilm, a symbiotic polymicrobial ecosystem that lines the mucosal surfaces, is the first line of defense against pathogenic strains that might otherwise dominate, and is therefore of critical importance for health. PMNs regularly interact with the commensal flora at the mucosal tissues in health and limit their growth without developing an overt inflammatory reaction to them. These PMNs exhibit what is called a para-inflammatory phenotype, and have reduced inflammatory output. When biofilm growth and makeup are disrupted (i.e., dysbiosis), clinical symptoms associated with acute and chronic inflammatory responses to these changes may include pain, erythema and swelling. However, in most cases, these responses indicate that the immune system is functioning properly to re-establish homeostasis and protect the status quo. Defects in this healthy everyday function occur as a result of PMN subversion by pathological microbial strains, genetic defects or crosstalk with other chronic inflammatory conditions, including cancer and rheumatic disease, and this can provide some avenues for therapeutic targeting of PMN function. In other cases, targeting PMN functions could worsen the disease state. Certain PMN-mediated responses to pathogens, for example Neutrophil Extracellular Traps (NETs), might lead to undesirable symptoms such as pain or swelling and tissue damage/fibrosis. Despite collateral damage, these PMN responses limit pathogen dissemination and more severe damage that would otherwise occur. New data suggests the existence of unique PMN subsets, commonly associated with functional diversification in response to particular inflammatory challenges. PMN-directed therapeutic approaches depend on a greater understanding of this diversity. Here we outline the current understanding of PMNs in health and disease, with an emphasis on the positive manifestations of tissue and organ-protective PMN-mediated inflammation.

Low-Density Neutrophils in Healthy Individuals Display a Mature Primed Phenotype

“…Neutrophils represent the most abundant leukocytes in blood and are considered the first line of defense during inflammation and infection (49)(50)(51). At damaged tissues neutrophils display several antimicrobial functions (4) including degranulation (7,8), production of reactive oxygen species (ROS) (52,53), phagocytosis (6) and the formation of neutrophil extracellular traps (NET) (9).…”

Inflammasomes in Alveolar Bone Loss

“…Neutrophils have protective functions to maintain homeostasis and resolve inflammation by secreting anti-inflammatory resolvins and sequestering pro-inflammatory factors. However, their hyperactive actions triggered by infection or injury may also cause tissue destruction with massive upregulation of pro-inflammatory cytokines in the circulation and tissue ( 134 ). Although neutrophils have a short life span due to apoptosis, their continuous replacement ensures robust capacity in host resistance against invading microorganisms and in tissue destruction, such as alveolar bone loss in periodontitis ( 2 ).…”

The Antibody Receptor Fc Gamma Receptor IIIb Induces Calcium Entry via Transient Receptor Potential Melastatin 2 in Human Neutrophils

“…Neutrophils represent the most abundant leukocytes in blood and are considered the first line of defense against invading microorganisms because they are the first leukocytes to arrive at sites of inflammation and infection ( 63 – 65 ). At affected sites neutrophils display several antimicrobial functions ( 66 ) including degranulation, production of reactive oxygen species (ROS) ( 67 , 68 ), phagocytosis ( 4 ) and the formation of neutrophil extracellular traps (NET) ( 5 ).…”