Neutrophils, the Felons of the Brain.

See related articles, p e40, e44 Polymorphonuclear neutrophils (PMNs) are short-lived but powerful immune cells, providing an early and robust inflammatory response after tissue damage. While the defensive role of PMNs in antimicrobial immunity has long been studied, recent attention has focused on the role of these cells in sterile inflammation after tissue injury. After stroke, PMNs are rapidly recruited to the injured brain. PMNs have been hypothesized to worsen stroke pathology via several mechanisms, including (1) physical blockade within the microvascular network, further reducing cerebral blood flow and (2) direct entry into the brain parenchyma, followed by the release of granules containing antimicrobial enzymes and chemical species that could further injury brain tissue. Based on these assumptions, the prevention of PMN entry into the brain after stroke has been extensively studied as a therapeutic target. Although PMN suppressing therapies showed benefit in numerous preclinical studies, subsequent clinical trials in stroke patients showed no overall benefit. Recently, a growing body of evidence has suggested that PMNs, like other immune cells, may exhibit some level of functional plasticity, analogous to Th1/Th2 (for T cells), M1/ M2 (for macrophages/microglia; Mφ). The N1 PMN phenotype refers to PMNs with stronger proinflammatory/oxidative properties, which possess effective antitumor and antimicrobial actions and may cause greater detrimental effects in the stroke-affected brain. Assuming that the majority of circulating neutrophils are normally in the N1 state, to maximize their ability to effectively engage in antimicrobial activities, the PMNs entering the brain early after stroke may be primarily detrimental. Conversely, the N2 PMN phenotype is characterized by reduced proinflammatory properties and a higher content of beneficial molecules. As such, it is possible that the effect of PNMs on stroke outcome could depend on N1/N2 ratio, which may change with time after stroke, reducing the detrimental effects of infiltrating PMNs—or potentially even conferring benefit to the damaged tissue. Potential mechanisms of PMN-mediated benefit in stroke may involve (1) modification of other cells like macrophages (Mφ) and microglia to an anti-inflammatory healing phenotype, (2) PMN self-limitation of proinflammatory factors, or (3) direct secretion of beneficial factors. Some recent examples of these PMN behaviors after stroke are outlined below. Mature segmented neutrophils egress out of bone marrow to the blood circulation where they have short half-life (13–19 hours), meaning that all circulating PMNs are normally replaced within ≈ 1 day of their release. After tissue injury, including stroke, PMNs are recruited to the side of injury within hours, and continue for days, where they release some of their granule contents. Typically, PMNs then die via apoptosis and are consequently removed via Mφ-mediated efferocytosis (phagocytosis-mediated engulfment of apoptotic cells), which is essential to prevent PMN secondary necrosis with subsequent release of cytotoxic and proinflammatory PMN content. The efferocytosis of PMNs has been shown to induce an anti-inflammatory phenotype in the microglia and Mφ that phagocytose them. Thus, PMN death through apoptosis is believed to act as a signal for Mφ to acquire the M2 phenotype that is essential for efficient phagocytosis and improved healing. PMNs have also been shown to phagocytose themselves, a type of cannibalism which results in increased production of TGF-β (transforming growth factor β) by the engulfing PMN. TGF-β is a cytokine that acts as an inducer of N2 polarization and has been shown to reduce neuroinflammation and improve recovery after intracerebral hemorrhage (ICH). Thus, the proper clearance of apoptotic PMNs may assist in the resolution of inflammation and the promotion of tissue repair. Activation of the PPARγ (peroxisome proliferator-activated receptor-γ) promotes the conversion of Mφ to a healing (M2) phenotype. Cuartero et al recently showed that mice subjected to cerebral ischemia and treated with a PPARγ agonist, rosiglitazone, experienced enhanced PMN infiltration into the brain, and increased proportion of N2 (Ym1+; a prototypic marker of M2 phenotype) anti-inflammatory PMNs and reduced infarct volume. Importantly, Ym1+ PMNs were more effectively phagocytosed by Mφ, and systemic depletion of PMNs before stroke abolished the neuroprotective effect of PPARγ agonist treatment. Under in vitro conditions, PMNs stimulated with proinflammatory TNF-α or lipopolysaccharide produce and secrete Basic Science Controversy