BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia

Carrington, Emma M.; Louis, Cynthia; Kratina, Tobias; Hancock, Manuela S.; Keenan, Christine R.; Iannarella, Nadia; Allan, Rhys S.; Wardak, Ahmad; Czabotar, P.E.; Herold, Marco J.; Schenk, Robyn L; White, Christine; D'Silva, Damian B; Yang, Yuyan; Wong, Wesley; Wong, Huon L.; Bryant, Vanessa L.; Huntington, Nicholas; Rautela, Jai; Sutherland, Robyn M.; Zhan, Yifan; Hansen, Jacinta; Nhu, Duong; Lessène, Guillaume; Wicks, Ian P.; Lew, Andrew M.

doi:10.1182/bloodadvances.2020004139

Cited by 10 publications

(7 citation statements)

References 76 publications

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“…The percentage of karyorrhectic and karyolitic cells were higher in SF from RA patients with respect to the samples collected from the other groups and was positively associated with WBC count and the levels of IL-1β, IL-8, IL-10, TNF, and TGFβ. We found that neutrophils were characterized by the greatest frequency of pyknosis, and it is known that PMN actively contributes to tissue damage in inflammatory arthritis [ 19 , 20 ]. Apoptosis is a controlled form of cell death that minimizes the risk of collateral damage to surrounding tissues by leukocytes, in particular PMN [ 19 , 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Anti-apoptotic members, such as Bcl-2 bind to the pro-apoptotic effectors BAX/BAK, preventing their activation. Diverse stimuli can induce the BH3-only proteins (BID, BIM), which selectively compete for binding with the anti-apoptotic proteins, thus, facilitating the release of BAX/BAK, which consequently leads to the activation of caspases and cell destruction [ 20 , 24 ]. The genetic expression analysis was carried out using total RNA extraction, and it reflects the expression of leukocytes present in the SF.…”

Section: Discussionmentioning

confidence: 99%

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Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Baggio

Luisetto

Boscaro

et al. 2023

IJMS

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Genome damage has been related to the induction of autoimmune processes, chronic inflammation, and apoptosis. Recent studies suggest that some rheumatological diseases are associated with overall genomic instability in the T cell compartment. However, no data regarding leucocyte abnormalities in synovial fluid (SF) and their relationship with inflammation are available. The aim of this study was to investigate cellular phenotypes in SF collected from patients with different inflammatory arthropathies, including rhematoid arthritis (RA), psoriatic arthritis (PsA), crystal-induced arthritis (CIA), and non-inflammatory arthropathies, such as osteoarthritis (OA). We found high percentage of micronuclei in SF from CIA compared to the other groups and a high frequency of pyknotic cell in RA and CIA patients. A correlation between pyknosis and immature polymorphonuclear cells with local inflammatory indices was observed. The study of the apoptosis process revealed an increased BAX expression in CIA and RA compared to OA and PsA, while Bcl-2 was higher in CIA. Caspase-3 activity was increased in SF from RA patients and correlates with inflammatory and anti-inflammatory cytokines. In conclusion, our results showed that inflammatory SF is associated with genomic instability and abnormal cell subsets.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Baggio

Luisetto

Boscaro

et al. 2023

IJMS

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“…Therapeutic induction of neutrophil apoptosis at the site of inflammation may act to reduce aberrant inflammatory processes mediated by neutrophils in severe COVID-19. Neutrophils rely heavily on pro-survival BCL-2 family members for survival [ 190 ] and may be preferentially sacrificed with BH3 mimetic drugs that lower the threshold for the induction of intrinsic apoptosis. The rationale for killing activated neutrophils is supported by their involvement in producing pathogenic extracellular traps [ 67 ].…”

Section: Therapeuticsmentioning

confidence: 99%

Programmed cell death: the pathways to severe COVID-19?

Bader

Cooney

Pellegrini

et al. 2022

Biochemical Journal

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Two years after the emergence of SARS-CoV-2, our understanding of COVID-19 disease pathogenesis is still incomplete. Despite unprecedented global collaborative scientific efforts and rapid vaccine development, an uneven vaccine roll-out and the emergence of novel variants of concern such as omicron underscore the critical importance of identifying the mechanisms that contribute to this disease. Overt inflammation and cell death have been proposed to be central drivers of severe pathology in COVID-19 patients and their pathways and molecular components therefore present promising targets for host-directed therapeutics. In our review, we summarize the current knowledge on the role and impact of diverse programmed cell death (PCD) pathways on COVID-19 disease. We dissect the complex connection of cell death and inflammatory signaling at the cellular and molecular level and identify a number of critical questions that remain to be addressed. We provide rationale for targeting of cell death as potential COVID-19 treatment and provide an overview of current therapeutics that could potentially enter clinical trials in the near future.

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“…[39][40][41]43,44 However, in a recent study, increased apoptosis of PB neutrophils did not affect the blood ANC. 45,46 Anecdotal demonstration of phagocytosis/emperipolesis of neutrophils bymacrophages in the AIN BM needs quantitative data to explain a massive cell removal in AIN. 47…”

Section: Do Autoantibodies To Neutrophils Cause the Np?mentioning

confidence: 99%

Autoimmune Neutropenias: Update on Clinical and Biological Features in Children and Adults

et al. 2022

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The definition of autoimmune neutropenias (AIN) has been based on the demonstration of autoantibodies directed to various epitopes on blood neutrophils. However, this definition is probably too limited and excludes neutropenias (NPs) with a negative autoantibody test but with other phenomena that indicate an underlying autoimmune process. Examples of such AINs may be complete or incomplete systemic lupus erythematosus or other autoimmune diseases where NP is common but patients may not fulfill formal diagnostic criteria for a rheumatic disease. Recently, various inherited immune-dysregulation syndromes, such as those related to variants in, for example, TACI, BAFFR, ACKR1/DARC, LRBA, CTLA 4 genes, with dysregulated B- and T-lymphocyte functions, have been associated with concomitant AINs. Cellular immune mechanisms may also play a prominent role in the development of NP, in the presence or not of autoantibodies, in cases of large granular lymphocyte syndromes of T- and NK-cell types or in chronic idiopathic NP, particularly in adults with T-cell clonal populations. The course of AIN may differ according to age, being transient and rather uncomplicated in children, and chronic with treatment requirement in adolescents and adults. This review discusses current knowledge of AINs, including diagnostic procedures, treatments, and prognosis.

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BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia

Cited by 10 publications

References 76 publications

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Leucocyte Abnormalities in Synovial Fluid of Degenerative and Inflammatory Arthropathies

Programmed cell death: the pathways to severe COVID-19?

Autoimmune Neutropenias: Update on Clinical and Biological Features in Children and Adults

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