Patients with systemic sclerosis show phenotypic and functional defects in neutrophils

Impellizzieri, Daniela; Egholm, Cecilie; Valaperti, Alan; Distler, Oliver; Boyman, Onur

doi:10.1111/all.15073

Cited by 17 publications

(12 citation statements)

References 43 publications

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“…Although a lack of neutrophils in the skin could explain the recurrent bacterial infections in patients with AD and allergies, neutrophils of allergic patients have also been found to be impaired in terms of NET production and the chemokine receptors CXCR1 and CXCR2 ( 12 ). Similar findings have been made recently in patients with systemic sclerosis (SSc), an autoimmune disease with signs of type 2 immune skewing ( 44 ). In light of our data presented here, we suggest that the neutrophils in allergic patients and in SSc adopt a more aged phenotype.…”

Section: Discussionsupporting

confidence: 85%

Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection

et al. 2022

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Atopic individuals show enhanced type 2 immune cell responses and a susceptibility to infections with certain bacteria and viruses. Although patients with allergic diseases harbor normal counts of circulating neutrophils, these cells exert deficient effector functions. However, the underlying mechanism of this dysregulation of neutrophils remains ill defined. Here, we find that development, aging, and elimination of neutrophils are accelerated in mice with a predisposition to type 2 immunity, which, in turn, causes susceptibility to infection with several bacteria. Neutrophil-mediated immunity to bacterial infection was greatly decreased in mice with a genetic or induced bias to type 2 immunity. Abrogation of interleukin-4 (IL-4) receptor signaling in these animals fully restored their antibacterial defense, which largely depended on Ly6G+neutrophils. IL-4 signals accelerated the maturation of neutrophils in the bone marrow and caused their rapid release to the circulation and periphery. IL-4–stimulated neutrophils aged more rapidly in the periphery, as evidenced by their phenotypic and functional changes, including their decreased phagocytosis of bacterial particles. Moreover, neutrophils from type 2 immune predisposed mice were eliminated at a higher rate by apoptosis and phagocytosis by macrophages and dendritic cells. Collectively, IL-4 signaling–mediated neutrophil aging constitutes an important adaptive deficiency in type 2 inflammation, contributing to recurrent bacterial infections.

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Section: Discussionsupporting

confidence: 85%

Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection

et al. 2022

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“…90 Phenotypically, SSc neutrophils expressed lower levels of CD62L, CXCR1, and CXCR2, and lacked intracellular MPO reserves compared to neutrophils of healthy controls. 130 Interestingly, SSc neutrophils also exhibited an increase in STAT6 phosphorylation, 130 a pathway associated with IL-4 and IL-13 receptor signaling, indicating a possible neutrophil antagonism, similar to what has been reported in allergic diseases. 90 Another mechanism by which neutrophils perpetuate autoimmunity is the exposure of intracellular antigens to extracellular space through NETs, ROS, and degranulation (Figure 4).…”

Section: Box 2 Future Research Perspectivessupporting

confidence: 65%

“…Recent evidence suggested that neutrophils in systemic sclerosis (SSc) patients featured functional defects, including impairment of chemotaxis, phagocytosis, and NET release, 130 as seen in allergic diseases 90 . Phenotypically, SSc neutrophils expressed lower levels of CD62L, CXCR1, and CXCR2, and lacked intracellular MPO reserves compared to neutrophils of healthy controls 130 . Interestingly, SSc neutrophils also exhibited an increase in STAT6 phosphorylation, 130 a pathway associated with IL‐4 and IL‐13 receptor signaling, indicating a possible neutrophil antagonism, similar to what has been reported in allergic diseases 90 …”

Section: Neutrophils In Autoinflammation and Autoimmunitymentioning

confidence: 99%

Mechanisms regulating neutrophil responses in immunity, allergy, and autoimmunity

Özcan

Boyman

2022

Allergy

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Neutrophil granulocytes, or neutrophils, are the most abundant circulating leukocytes in humans and indispensable for antimicrobial immunity, as exemplified in patients with inborn and acquired defects of neutrophils. Neutrophils were long regarded as the foot soldiers of the immune system, solely destined to execute a set of effector functions against invading pathogens before undergoing apoptosis, the latter of which was ascribed to their short life span. This simplistic understanding of neutrophils has now been revised on the basis of insights gained from the use of mouse models and single-cell high-throughput techniques, revealing tissue-and context-specific roles of neutrophils in guiding immune responses. These studies also demonstrated that neutrophil responses were controlled by sophisticated feedback mechanisms, including directed chemotaxis of neutrophils to tissue-draining lymph nodes resulting in modulation of antimicrobial immunity and inflammation. Moreover, findings in mice and humans showed that neutrophil responses adapted to different deterministic cytokine signals, which controlled their migration and effector function as well as, notably, their biologic clock by affecting the kinetics of their aging. These mechanistic insights have important implications for health and disease in humans, particularly, in allergic diseases, such as atopic dermatitis and allergic asthma bronchiale, as well as in autoinflammatory and autoimmune diseases. Hence, our improved understanding of neutrophils sheds light on novel therapeutic avenues, focusing on molecularly defined biologic agents.

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“…In PBMCs, CD62L has been found to be similar in the SSc and HC subjects [8], whereas opposing results have been reported for CD62L+ Tregs [35,36]. A lower surface expression of CD62L was found in the neutrophils [37] and NK cells [38] of SSc patients and in the CD3 T cells in SSc patients with PAH [39]; however, in those cell types, CD62L exhibited different functions than on monocytes. This indicates cell-type specific regulation of CD62L levels.…”

Section: Discussionmentioning

confidence: 90%

Increased L-Selectin on Monocytes Is Linked to the Autoantibody Profile in Systemic Sclerosis

Brezovec

Perdan-Pirkmajer

Kuret

et al. 2022

IJMS

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Monocytes are known to be implicated in the pathogenesis of systemic sclerosis (SSc), as they exert prominent migratory, adhesive, and chemotactic properties. The aim of our study was to characterize the surface expression of adhesion/chemotactic molecules (CD62L, CD11b, CCR2, CCR5) on the SSc monocytes and determine correlations with the clinical presentation of SSc. We included 38 SSc patients and 36 healthy age-and sex-matched controls. Isolated monocytes, as well as in vitro serum-treated monocytes, were analyzed by flow cytometry; additionally, soluble CD62L was measured in serum. We found increased soluble CD62L in the SSc serum samples and increased CD62L on the surface of the SSc monocytes in the in the same set of patients. Among samples with determined SSc-specific autoantibodies, the surface CD62L was the lowest in patients positive for anti-PM/Scl autoantibodies and the highest in patients with anti-topoisomerase I autoantibodies (ATA). The treatment of isolated healthy monocytes with ATA-positive SSc serum resulted in increased surface CD62L expression. Moreover, surface CCR5 was reduced on the monocytes from SSc patients with interstitial lung disease but also, along with CCR2, negatively correlated with the use of analgesics/anti-inflammatory drugs and immunosuppressants. In conclusion, increased CD62L on SSc monocytes, particularly in ATA-positive patients, provides new insights into the pathogenesis of SSc and suggests CD62L as a potential therapeutic target.

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Patients with systemic sclerosis show phenotypic and functional defects in neutrophils

Cited by 17 publications

References 43 publications

Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection

Type 2 immune predisposition results in accelerated neutrophil aging causing susceptibility to bacterial infection

Mechanisms regulating neutrophil responses in immunity, allergy, and autoimmunity

Increased L-Selectin on Monocytes Is Linked to the Autoantibody Profile in Systemic Sclerosis

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