More friend than foe: the emerging role of neutrophils in tissue repair

Peiseler, Moritz; Kubes, Paul

doi:10.1172/jci124616

Cited by 265 publications

(269 citation statements)

References 152 publications

(188 reference statements)

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“…by promoting angiogenesis (6). Initially defined as a homogeneous population of sentinels constituting a first line of defense against invading microorganisms, recent research has highlighted the functional heterogeneity of neutrophils in mice and humans (7), (8), (9). How neutrophil functional heterogeneity is shaped by specific tissue niches, and in distinct pathological settings is still poorly understood (7), (8), (9).…”

Section: Introductionmentioning

confidence: 99%

“…Initially defined as a homogeneous population of sentinels constituting a first line of defense against invading microorganisms, recent research has highlighted the functional heterogeneity of neutrophils in mice and humans (7), (8), (9). How neutrophil functional heterogeneity is shaped by specific tissue niches, and in distinct pathological settings is still poorly understood (7), (8), (9). In MI, a process of temporal neutrophil polarization has been suggested, with N1 polarized proinflammatory neutrophils infiltrating the heart early after MI (day1), while at day 5 and 7 the proportion of N2 polarized anti-inflammatory neutrophils increases (10).…”

Section: Introductionmentioning

confidence: 99%

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Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

Vafadarnejad

Rizzo

Krampert

et al. 2019

Preprint

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Objective-After myocardial infarction, neutrophils rapidly and massively infiltrate the heart, where they can promote both tissue healing and damage. Here, we investigated the dynamics of cardiac neutrophil heterogeneity after infarction.Methods and results-We employed single-cell transcriptomics (scRNA-seq) to investigate temporal neutrophil heterogeneity in the heart after murine myocardial infarction. At day 1, 3, and 5 after infarction, neutrophils could be delineated into six distinct clusters with specific time-dependent patterning and proportions. While the majority of neutrophils at day 1 were characterized by high expression of chemokines (e.g. Cxcl3, Ccl6), and putative activity of transcriptional regulators involved in hypoxic response (Hif1a) and emergency granulopoiesis (Cebpb), two major subsets of Siglecf hi (enriched for e.g. Icam1 and Tnf) and Siglecf low (Slpi, Ifitm1) neutrophils were found at 3 and 5 days. Flow cytometry analysis confirmed the presence of LY6G + SIGLECF hi and LY6G + SIGLECF low neutrophils in the heart from 3 days after infarction onwards. LY6G + SIGLECF hi neutrophils were absent from the bone marrow, blood and spleen, suggesting local acquisition of surface SIGLECF. Acquisition of the SIGLECF hi state was paralleled by features of neutrophil ageing and activation (ICAM1 hi CXCR4 hi CD49d hi CD62L low ). scRNA-seq of atherosclerotic aortas revealed two neutrophil subsets with gene expression patterns reminiscent of the major Siglecf hi and Siglecf low cardiac neutrophil subpopulations, revealing that these populations may be present across distinct contexts of cardiovascular inflammation.Conclusion-Altogether, our data provide a time-resolved census of neutrophil diversity and gene expression dynamics in the mouse ischemic heart at the single-cell level, and suggests that temporal neutrophil heterogeneity is in part driven by local transition to a SIGLECF hi state.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

Vafadarnejad

Rizzo

Krampert

et al. 2019

Preprint

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“…Thus, ATP gating of P2X7R with the subsequent assembly of the NLRP3 inflammasome/caspase-1 complex is critical for IL-1β maturation as well as its release [295]. Human neutrophils, which play an important role in tissue damage and repair, release ATP from the leading edge of the cell surface to amplify chemotactic signals and direct cell orientation and migration by feedback through P2Y2 nucleotide receptors [293,296]. Thus, ATP release and autocrine feedback through P2Y2 and A3 receptors provide signal amplification, controlling gradient sensing and migration of neutrophils [293].…”

Section: Adenosine Triphosphatementioning

confidence: 99%

Damage-associated molecular patterns in trauma

Relja

Land

2019

Eur J Trauma Emerg Surg

135

131

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In 1994, the "danger model" argued that adaptive immune responses are driven rather by molecules released upon tissue damage than by the recognition of "strange" molecules. Thus, an alternative to the "self versus non-self recognition model" has been provided. The model, which suggests that the immune system discriminates dangerous from safe molecules, has established the basis for the future designation of damage-associated molecular patterns (DAMPs), a term that was coined by Walter G. Land, Seong, and Matzinger. The pathological importance of DAMPs is barely somewhere else evident as in the posttraumatic or post-surgical inflammation and regeneration. Since DAMPs have been identified to trigger specific immune responses and inflammation, which is not necessarily detrimental but also regenerative, it still remains difficult to describe their "friend or foe" role in the posttraumatic immunogenicity and healing process. DAMPs can be used as biomarkers to indicate and/or to monitor a disease or injury severity, but they also may serve as clinically applicable parameters for optimized indication of the timing for, i.e., secondary surgeries. While experimental studies allow the detection of these biomarkers on different levels including cellular, tissue, and circulatory milieu, this is not always easily transferable to the human situation. Thus, in this review, we focus on the recent literature dealing with the pathophysiological importance of DAMPs after traumatic injury. Since dysregulated inflammation in traumatized patients always implies disturbed resolution of inflammation, so-called model of suppressing/inhibiting inducible DAMPs (SAMPs) will be very briefly introduced. Thus, an update on this topic in the field of trauma will be provided.

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“…The last 20 years have seen a fundamental shift in our understanding of the roles and capabilities of neutrophils. We are now aware that they can live for much longer than previously thought (up to 5 or 6 days in vivo [1]); that they move into lymphatics, both during inflammation and as part of regular homeostatic control [2][3][4][5][6][7][8]; that they can have reparative as well as pro-inflammatory roles [9][10][11][12][13][14]; and that they influence outcomes in chronic inflammatory and autoimmune diseases, as well as infections [15][16][17]. As a result, we now recognise neutrophils as able to influence and shape adaptive immunity in tissues and in lymph nodes, in both suppressive and activatory manners (reviewed in [18,19]).…”

Section: Introductionmentioning

confidence: 99%

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

Minns

Smith

Alessandrini

et al. 2020

Preprint

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The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic cell death; it has potent antibacterial, antiviral and antifungal activity as well as being a powerful immunomodulator. It is released in proximity to CD4 + T cells during inflammatory and infectious disease but its impact on T cell phenotype is scarcely understood. Here we demonstrate that cathelicidin is a powerful Th17 potentiating factor which increases expression of the aryl hydrocarbon receptor (AHR) and the RORγt transcription factor, in a TGF-β1-dependent manner. We show that cathelicidin induces IL-17F production in particular, and that its induction of IL-17A+F+ double producing cells is dependent on AHR while its induction of IL-17F single producing cells is not. In the presence of TGF-β1, cathelicidin profoundly suppressed IL-2 and down-regulated T-bet, specifically directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1 cells were protected from apoptotic death by cathelicidin, in the first example of a neutrophil-released mediator inducing survival of a T cell subset. Finally, we show that cathelicidin is released by neutrophils in mouse lymph nodes following inoculation of heat-killed Salmonella typhimurium and that cathelicidin-deficient mice have suppressed Th17 responses during inflammation, but not at steady state. We propose that the release of cathelicidin by neutrophils is required for maximal Th17 differentiation and IL-17 production by CD4 + T cells, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses with some sophistication.

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More friend than foe: the emerging role of neutrophils in tissue repair

Cited by 265 publications

References 152 publications

Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

Damage-associated molecular patterns in trauma

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

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