The inhibitory receptor CD300a is essential for neutrophil‐mediated clearance of urinary tract infection in mice

Isaacson, Batya; Baron, Maya; Yamin, Rachel; Bachrach, Gilad; Levi‐Schaffer, Francesca; Granot, Zvi; Mandelboim, Ofer

doi:10.1002/eji.202049006

Cited by 4 publications

(6 citation statements)

References 21 publications

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“…This is not surprising, since also in a previous report no differences were found between WT and CD300a −/− ability to phagocytize apoptotic cells in C57BL mice [14]. However, in previous reports, CD300a −/− mice presented with impaired phagocytosis of fluorescent beads by neutrophils [18] and defective efferocytosis of apoptotic neutrophils by peritoneal MΦ [19]. It is possible that CD300a differentially influences phagocytosis and efferocytosis on different cells according to the target employed (beads or apoptotic cells).…”

Section: Discussionmentioning

confidence: 56%

CD300a Regulates Mouse Macrophage Functionality in Allergic Inflammation

Puzzovio

Levy

Levi‐Schaffer

2023

Int Arch Allergy Immunol

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Background: CD300a is an inhibitory receptor (IR) expressed on several leukocytes, including mast cells (MCs) and macrophages (MΦ), important cells in allergic inflammation (AI). We have previously characterized CD300a role on MCs and in vivo in mouse models of allergy, in which the absence of CD300a resulted in increased inflammatory features and delayed resolution. However, the exact mechanism of this delayed resolution is unclear. Our hypothesis is that MΦ, important players in resolution, might be impaired when CD300a is absent. Objectives: The aim of the study was to investigate CD300a-dependent functionality of mouse MΦ. Method: MΦ were purified from the peritoneum of wild-type (WT) and CD300a−/− mice naïve and 48 h and 96 h after challenge with ovalbumin/alum. Phenotype switching was analyzed via specific M1-M2 inducers and markers. MΦ phagocytotic ability was assessed via Staphylococcus aureus pHrodo-conjugated bioparticles. The influence of MCs on MΦ was investigated by incubating WT MΦ with supernatants from non-activated and IgE-activated bone marrow-derived MCs (BMMCs) and analyzing functional responses. Results: Naïve CD300a−/− MΦ presented with increased sensitivity to activation when treated with LPS. Absence of CD300a results in increased Arg1 expression and increased IL-6 release when MΦ are purified from allergic peritonitis-induced mice. Similar results were obtained when CD300a−/− MΦ were purified 96 h after challenge. On the other hand, CD300a absence did not affect phagocytosis. WT MΦ incubated with supernatants of non-activated and IgE-activated BMMCs presented with increased iNOS expression and decreased Arg1 levels. Conclusions: The IR CD300a controls the activation state of MΦ, and its absence could augment the inflammatory state seen in CD300a−/− mice. Moreover, MCs can also influence MΦ phenotype switching. This may partially explain the delayed AI resolution seen in these mice.

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Section: Discussionmentioning

confidence: 56%

CD300a Regulates Mouse Macrophage Functionality in Allergic Inflammation

Puzzovio

Levy

Levi‐Schaffer

2023

Int Arch Allergy Immunol

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“…Under the basal epithelium, the resident mast cells, NK cells, Ly6C − macrophages, and 𝛾𝛿T cells function as sentinels to sense UPEC infection, and neutrophils and Ly6C + macrophages are further recruited into the bladder to eliminate the bacteria. [17,23,[31][32][33][34][35] ILCs play a critical role in the host defense against pathogens in other barrier tissues, such as the gut, lung, and skin, [12,13] and it has been reported that CD4 + ILC3 levels are increased in the bladder of UPEC-infected mice. [36] However, whether bladder-resident ILCs respond to UPEC infection, and whether ILC3s play a crucial role in defending against UPEC during an infection, remain to be determined.…”

Section: Introductionmentioning

confidence: 99%

Group 3 Innate Lymphoid Cells Protect the Host from the Uropathogenic Escherichia coli Infection in the Bladder

Huang

et al. 2022

Advanced Science

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Innate lymphoid cells (ILCs) are crucial in orchestrating immunity and maintaining tissue homeostasis in various barrier tissues, but whether ILCs influence immune responses in the urinary tract remains poorly understood. Here, bladder‐resident ILCs are comprehensively explored and identified their unique phenotypic and developmental characteristics. Notably, bladder‐resident ILCs rapidly respond to uropathogenic Escherichia coli (UPEC) infection. It is found that ILC3 is necessary for early protection against UPEC infection in the bladder. Mechanistically, UPEC infection leads to interleukin (IL)‐1β production in the bladder via a MyD88‐dependent pathway, which promotes ILC3 activation. ILC3‐expressed IL‐17A further recruits neutrophils and controls UPEC infection in the bladder. Together, these results demonstrate a critical role for bladder ILCs in the host defense against UPEC infection.

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“…In this context, a major role is played by molecules that regulate the cellular innate immune signalling/response, in an event of phagocytic activity, thus preventing an excessive pro-inflammatory cytokine release that could compromise the BTB. We have recently shown, for the first time in Sertoli cells, a functional Nlrp3 inflammasome able to elicit pro-inflammatory cytokine response and cell death, upon stimulation of the NF-κB converging NOD1 and TLR4, in the presence of danger signal as ATP that could serve as a cornerstone for BTB disruption and potential infertility upon proper pathogenic stimulation [ 8 ]. We have also found that NOD1 challenge strongly upregulated the CD300a receptor (unpublished ), which recognizes phosphatidylserine and phosphatidylethanolamine presented on apoptotic cell membranes [ 8 ].…”

mentioning

confidence: 99%

“…We have recently shown, for the first time in Sertoli cells, a functional Nlrp3 inflammasome able to elicit pro-inflammatory cytokine response and cell death, upon stimulation of the NF-κB converging NOD1 and TLR4, in the presence of danger signal as ATP that could serve as a cornerstone for BTB disruption and potential infertility upon proper pathogenic stimulation [ 8 ]. We have also found that NOD1 challenge strongly upregulated the CD300a receptor (unpublished ), which recognizes phosphatidylserine and phosphatidylethanolamine presented on apoptotic cell membranes [ 8 ]. CD300a is a member of the CD300 type I trans-membrane glycoproteins, signalling via its ITIM motif and being regulated by internalization [ 9,10 ].…”

mentioning

confidence: 99%

“…CD300a is proptosis restrictive, affecting negatively both total and cleaved Gasdermin-D, meaning that CD300a might promote caspase-1 pathway, but again bi-directionally restrict massive cell death. Similarly, CD300a is considered negative regulator in other phagocytic cell types, as CD300a gene deletion in Ma results in a prolonged proinflammatory IL-6 secretion [ 7 ], but on the other hand, TLR4 activation in Ne, results in CD300a upregulation and strong ROS expression [ 4 ], as well as CD300a has been found crucial to fight off an UPEC in urogenital tract [ 8 ]. Thus, our data suggest that phagocytic receptor CD300a signalling perturbation could potentially impact Sertoli cell faith and antigen presentation via caspase-1 and caspase-3 activity modulation.…”

mentioning

confidence: 99%

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The Effect of CD300A Receptor on Caspase-1 Activity in the Context of Cell Death and on Its Activators Nlrp3 and Asc in Sertoli Cells

Tsvetkova

Tsvetankova

Todorova

et al. 2022

C. R. Acad. Bulg. Sci.

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The phagocytosis of spermatozoa cytoplasm by Sertoli cells is a key maturation event during spermiation and takes place in a blood-testis barrier maintained immune-privileged environment that is essential for the prevention of the sperm self-antigens from presentation. We have recently discovered Nlrp3 inflammasome to be functional in Sertoli cells upon TLR4 and NOD receptors challenge in ATP danger presence, resulting in release of pro-inflammatory cytokines and cell death that could potentially result in breaking of the selftolerance. In this context we have investigated, the considered inhibitory, phagocytic receptor CD300a that is able to detect eventually sperm cell surface apoptotic signals. We found CD300a to be essential for Nlrp3 inflammasome activation via CD300a-dependent Asc expression and both caspase-1 and caspase-3 activation, since its gene silencing abrogated these events. At the same time CD300a demonstrated bi-directional regulatory abilities, supressing Gasdermin D inflammasome effector pro- and activated forms. CD300a had a restrictive effect on cell population level reducing caspase positive cells in strong caspase-1 and 3, and weak caspase-3 expressing dead cells, suggesting key regulatory role in Sertoli cell faith. CD300a should be further explored as its potential perturbation could play a role in putative self-antigen-toleranceperturbation and thus contribute to male infertility.

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The inhibitory receptor CD300a is essential for neutrophil‐mediated clearance of urinary tract infection in mice

Cited by 4 publications

References 21 publications

CD300a Regulates Mouse Macrophage Functionality in Allergic Inflammation

CD300a Regulates Mouse Macrophage Functionality in Allergic Inflammation

Group 3 Innate Lymphoid Cells Protect the Host from the Uropathogenic Escherichia coli Infection in the Bladder

The Effect of CD300A Receptor on Caspase-1 Activity in the Context of Cell Death and on Its Activators Nlrp3 and Asc in Sertoli Cells

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