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Neutrophils are formidable defenders. Their vast numbers, constant production, high cytotoxicity and capacity to produce extracellular traps, underlie their ability to efficiently protect in a microorganism-rich world. However, neutrophils are much more than immune sentinels, as evidenced by the expanding repertoire of functions discovered in the context of tissue homeostasis, regeneration or chronic pathologies. In this Perspective, we discuss general functional features of the neutrophil compartment that may be relevant in most, if not all, physiological scenarios in which they participate, including specialization in naïve tissues, transcriptional noise in the bloodstream as a potential strategy for diversification and functional bias in inflammatory sites. We intentionally present the reader with more questions than answers and propose models and approaches that we hope will shed new light onto the biology of these fascinating cells and spark new directions of research.

Inflammatory memory cues initiated by neutrophils and bone marrow stroma suggest potential therapeutic targets for the treatment of multiple myeloma.

The functions of macrophages in healthy tissues extend beyond their well‐established roles as immune sentinels and effectors. Among tissues, cells of the brain and heart possess unique excitatory properties that likely demand special support. Accordingly, existing evidence demonstrates that microglia in the brain has an active role in synaptic organization, control of neuronal excitability, phagocytic removal of debris, and trophic support during brain development. In the heart, recent studies suggest that cardiac macrophages are involved in the regulation of heart homeostasis by phagocytosis, production of trophic, and immune‐related factors, and by forming direct contacts with cardiomyocytes to regulate electrical conduction. In this review, we discuss mechanisms associated with the high degree of specialization of resident macrophages in both tissues, their origin and heterogeneity, and their contributions in regulating homeostasis under steady‐state and pathological conditions. Review on the ontogeny and tissue specialized functions of microglia and cardiac macrophages and their role in heart and brain homeostasis and inflammation.

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PPARγ activation with RSG induces 5‐LO‐dependent CD36 expression in resident microglia that participates in resolution of inflammation by phagocytosis, in an experimental model of stroke. PPARγ‐achieved neuroprotection in experimental stroke has been explained by the inhibition of inflammatory genes, an action in which 5‐LO, Alox5, is involved. In addition, PPARγ is known to promote the expression of CD36, a scavenger receptor that binds lipoproteins and mediates bacterial recognition and also phagocytosis. As phagocytic clearance of neutrophils is a requisite for resolution of the inflammatory response, PPARγ‐induced CD36 expression might help to limit inflammatory tissue injury in stroke, an effect in which 5‐LO might also be involved. Homogenates, sections, and cellular suspensions were prepared from brains of WT and Alox5−/−mice exposed to distal pMCAO. BMMs were obtained from Lys‐M Cre+PPARγf/fand Lys‐M Cre−PPARγf/fmice. Stereological counting of double‐immunofluorescence‐labeled brain sections and FACS analysis of cell suspensions was performed. In vivo and in vitro phagocytosis of neutrophils by microglia/macrophages was analyzed. PPARγ activation with RSG induced CD36 expression in resident microglia. This process was mediated by the 5‐LO gene, which is induced in neurons by PPARγ activation and at least by one of its products—LXA4—which induced CD36 independently of PPARγ. Moreover, CD36 expression helped resolution of inflammation through phagocytosis, concomitantly to neuroprotection. Based on these findings, in addition to a direct modulation by PPARγ, we propose in brain a paracrine model by which products generated by neuronal 5‐LO, such as LXA4, increase the microglial expression of CD36 and promote tissue repair in pathologies with an inflammatory component, such as stroke.

Neutrophils have been traditionally recognized as major mediators of a deleterious inflammatory response in acute ischemic stroke, but their potential as a therapeutic target remains unexplored. Recent evidence indicates that neutrophils may acquire different phenotypes and contribute to resolution of inflammation through the release of anti-inflammatory mediators. Thus, similar to M2 macrophages, neutrophils have been proposed to shift toward an N2 phenotype, a polarization that is peroxisome proliferator-activated receptor- dependent in macrophages. We hypothesize that peroxisome proliferator-activated receptor- activation with rosiglitazone induces changes in neutrophilic mobilization and phenotype that might influence stroke outcome.

Sirtuin 1 (SIRT1) is a member of NAD-dependent protein deacetylases implicated in a wide range of cellular functions and has beneficial properties in pathologies including ischemiareperfusion processes and neurodegeneration. However, no direct evidence has been reported on the direct implication of SIRT1 in ischemic stroke. The aim of this study was to establish the role of SIRT1 in stroke using an experimental model in mice.