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. 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 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. 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. 3Department of Dental Oncology, Maxillofacial and Ocular Prosthetics, Princess Margaret Cancer Centre, Toronto, ON, CanadaThe role of polymorphonuclear neutrophils (PMNs) in biology is often recognized during pathogenesis associated with PMN hyper- or hypo-functionality in various disease states.Despite collateral damage, these PMN responses limit pathogen dissemination and more severe damage that would otherwise occur. 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. In other cases, targeting PMN functions could worsen the disease state. 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. However, in most cases, these responses indicate that the immune system is functioning properly to re-establish homeostasis and protect the status quo. 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.PMNs have evolved under rigorous biological constraints, as a balance is required between the need to respond appropriately to a wide range of threats and the extreme tissue destructive potential of PMN antimicrobial functions. This is in contrast to adaptive immune cells, which evolved ~100 million years later, in early vertebrates. Innate immune phagocytic cells are the most ancient immune cells, having evolved ~600 million years ago, in early invertebrate eukaryotes ( 1). 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.- PMNs are constitutively recruited to healthy mucosal tissues- PMNs prune the commensal biofilm to maintain homeostasis in the oral cavity- Dysbiosis contributes to hyper-inflammatory PMN responses and periodontal disease- Targeted therapies to suppress PMN hyper-inflammatory responses are available, but may not be appropriate in cases where PMN-mediated pathogen clearance is required IntroductionPolymorphonuclear neutrophils (PMNs) are the most abundant leukocytes in the circulation, and the first cellular responders to tissue injury and infection. PMN-directed therapeutic approaches depend on a greater understanding of this diversity.Once in the tissue, PMNs migrate toward the site of inflammation through highly sensitive detection of a shallow gradient of chemotactic agents and penetrate through the three-dimensional tissue matrix by secretion of tissue-digestive proteases ( 18). Furthermore, dysregulated PMN responses associated with excessive tissue damage ( 3, 4) are implicated in a wide array of chronic inflammatory diseases including periodontal disease ( 5, 6), cancer ( 7– 9), sepsis ( 10, 11), lupus ( 12), asthma ( 13), diabetes ( 14), and rheumatologic diseases ( 15, 16).PMNs are generated in the bone marrow by hematopoietic precursor cells and enter the circulation where they can then be recruited across the vascular barrier and into various tissues in response to specific chemotactic and pro-inflammatory signals, a process known as extravasation ( 17). In the vast majority of cases PMNs manage to respond suitably to preserve homeostasis and organismal health, however certain pathogenic bacteria have evolved to subvert or evade PMNs ( 2).
![]() ![]() ![]() The quality and magnitude of the PMN response will depend on the nature and abundance of the danger signals present. Through these PRRs, PMNs recognize and respond appropriately to a wide range of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). These mechanisms are elicited by a wide range of pathogens, which PMNs detect using an array of surface-expressed innate immune receptors, known as pattern-recognition receptors (PRRs) ( 21). PMNs have various tools for neutralizing pathogens including release of toxic enzymes and proteases through degranulation, secretion of reactive oxygen species (ROS), phagocytosis and pathogen killing within the phagosome, and secretion of euchromatic DNA in the form of Neutrophil Extracellular Traps (NETs) ( 20). As PMNs migrate through the tissue, they forge a pathway for migration of subsequently recruited cells and leave a trail of haptokinetic markers ( 19), which provide cues for directional recruitment of follower cells. Best vpn for mac 2018 freeThe presence of specific Staphylococcus aureus-derived virulence factors in a wound was shown to promote early PMN recruitment and favorably influence wound healing and closure ( 34). Analysis of the role of PMNs in wound healing suggests that they can either accelerate or impede the process, depending on the specific context ( 30– 33). Therefore, tissue PMNs can act either to amplify or resolve the inflammation. PMN secreted NETs can also contribute to resolution through sequestration and turnover of pro-inflammatory factors ( 29). The diverse array of potential PMN activities includes wide-ranging interactions with innate and adaptive immune cells ( 25), which give PMNs the capacity to influence the progression and outcome of immune responses ( 26, 27).PMNs also play an essential role in the resolution of tissue inflammation through the secretion of anti-inflammatory lipid-based molecules, including resolvins ( 28). Best windows emulator for macIn the majority of studies, evidence of PMN diversity has been identified in disease states. In addition to our observation that a small population of circulating PMNs is primed for rapid recruitment to the tissues ( 41), other compelling evidence has emerged suggesting the presence of significant PMN heterogeneity ( 42– 48). However, there is a growing body of evidence that challenges these assumptions ( 40). Diversity of the PMN Response: Activation States or Subsets?Classically, PMNs have been considered a terminally differentiated and homogenous population with a limited lifespan ( 37), low transcriptional activity ( 38), and an inability to return to circulation after migration to tissues ( 39). Additionally, subsets of PMNs have been identified that ( 1) reverse transmigrate from the tissue into the circulation ( 35, 56– 58), ( 2) can migrate to local lymph nodes and perform antigen presentation to T-cells ( 59, 60), and ( 3) stimulate marginal zone splenic B-cells to produce diversified immunoglobulins ( 61).Although different PMN phenotypes have been identified based on differences in functionality and cell surface marker expression, it is currently unclear as to whether these constitute differentiated subsets of cells, or simply PMNs that have changed their activation state in a developmental manner and in response to specific stimuli. In cancer, distinct blood PMN subsets have been identified with opposing cancer-related functions and an ability to switch phenotypes ( 7, 55), which will be discussed in more detail below. Also, myeloid-derived suppressor cells (MDSCs), which are defined by their ability to suppress T-cell proliferation, have been identified in specific inflammatory disease states ( 54).
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