Regulation of steady-state neutrophil homeostasis by macrophages

Gordy, Claire; Pua, Heather H.; Sempowski, Gregory D.; He, You–Wen

doi:10.1182/blood-2010-01-265959

Cited by 95 publications

(116 citation statements)

References 35 publications

(45 reference statements)

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“…We looked into the difference between these two strains of mice that led to the inflammatory phenotype in c-FLIP f/f CD11c-Cre mice. G-CSF plays a pivotal role in the excess granulopoiesis in c-FLIP f/f Lysm-Cre mice (28). We found a profound increase in serum G-CSF levels in c-FLIP f/f CD11c-Cre mice (Fig.…”

Section: Differential Production Of G-csf May Account For Neutrophilimentioning

confidence: 53%

“…These results suggest that hemizygous deficiency of c-FLIP in DCs was insufficient to generate inflammation. Therefore, deletion of c-FLIP in DCs led to PMN elevation in bone marrow and the periphery, similar to c-FLIP CKO in macrophages (28).…”

Section: Cko Of C-flip In Dcs Leads To An Increase In Neutrophils Inmentioning

confidence: 99%

“…Therefore, deletion of c-FLIP in DCs led to elevation in polymorphonuclear neutrophils (PMNs) and reduction in B cells and Lin 2 cells in bone marrow, similar to mice with c-FLIP CKO in macrophages (28). Lysm-Cre mice (28). The percentage of pDCs and CD11b…”

Section: Cko Of C-flip In Dcs Leads To An Increase In Neutrophils Inmentioning

confidence: 99%

“…c-FLIP is highly expressed in mature DCs and is required to protect DCs from apoptosis (25,26). Notably, c-FLIP is essential for the survival of macrophages (27,28). In mice with c-FLIP conditional KO (CKO) in macrophages, no c-FLIP 2/2 macrophages are detectable (28,29).…”

mentioning

confidence: 99%

“…Notably, c-FLIP is essential for the survival of macrophages (27,28). In mice with c-FLIP conditional KO (CKO) in macrophages, no c-FLIP 2/2 macrophages are detectable (28,29). In contrast, an earlier study has shown that deletion of caspase-8, the c-FLIP-binding partner, impairs macrophage development but exhibits little effect on DC differentiation (30), suggesting a difference between macrophages and DCs in their sensitivity to caspase-8/c-FLIP deficiency.…”

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confidence: 99%

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Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

et al. 2015

The Journal of Immunology

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Cellular FLIP (c-FLIP) specifically inhibits caspase-8 and suppresses death receptor–induced apoptosis. c-FLIP has also been reported to transmit activation signals. In this study, we report a novel function of c-FLIP involving inhibition of myeloid cell activation through antagonizing the selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells (DCs) led to neutrophilia and splenomegaly. Peripheral DC populations, including CD11b+ conventional DCs (cDCs), CD8+ cDCs, and plasmacytoid DCs, were not affected by c-FLIP deficiency. We also found that c-FLIP knockout cDCs, plasmacytoid DCs, and bone marrow–derived DCs (BMDCs) displayed enhanced production of TNF-α, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and dectin-1. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP–deficient BMDCs could be partly linked to an elevated activation of p38 MAPK after engagement of innate receptors. Increased activation was also found in c-FLIP+/− macrophages. Additionally, the increased activation in c-FLIP–deficient DCs was independent of caspase-8. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Additionally, our observations suggest that cancer therapy targeting c-FLIP downregulation may facilitate DC activation and increase T cell immunity.

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Section: Differential Production Of G-csf May Account For Neutrophilimentioning

confidence: 53%

Section: Cko Of C-flip In Dcs Leads To An Increase In Neutrophils Inmentioning

confidence: 99%

Section: Cko Of C-flip In Dcs Leads To An Increase In Neutrophils Inmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

et al. 2015

The Journal of Immunology

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Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas‐Induced Apoptosis–Transgenic Mice

McNeill

Goon

et al. 2017

Arthritis & Rheumatology

106

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Objective Macrophages are believed to play a critical role in the inflammation associated with the development of osteoarthritis (OA) in obesity. The objective of the study was to investigate whether short-term, systemic depletion of macrophages would mitigate OA following injury in obese mice. Methods CSF-1R–GFP+ Macrophage Fas-Induced Apoptosis (MaFIA) transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effect of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and microCT. Immunohistochemistry was used to identify various immune cells. Serum and synovial fluid cytokines were also measured. Results Macrophage-depleted mice had significantly fewer M1 and M2 macrophages in the surgical operated-joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate OA with obesity; instead, it induced systemic inflammation and led to a massive infiltration of CD3+ T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage-depleted mice also demonstrated markedly increased pro-inflammatory cytokines including granulocyte-colony stimulating factor (G-CSF), IL-1β, IL-6, IL-8, and TNF-α in both serum and joint synovial fluid, although animals showed trends for decreased serum insulin and leptin levels after depletion. Conclusion Our findings indicate that macrophages are vital in modulating the homeostasis of immune cells in obesity and suggest that more targeted approaches of different macrophage subtypes may be necessary to mitigate inflammation and OA with obesity.

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Declining neutrophil production despite increasing G-CSF levels is associated with chronic inflammation in elderly rhesus macaques

Fahlberg

Takahashi

et al. 2021

Journal of Leukocyte Biology

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Aging is characterized by a loss of bone marrow hematopoietic tissue, systemic chronic inflammation, and higher susceptibility to infectious and noninfectious diseases. We previously reported the tightly regulated kinetics and massive daily production of neutrophils during homeostasis in adult rhesus macaques aged 3 to 19 yr (equivalent to approximately 10 to 70 yr of age in humans). In the current study, we observed an earlier release of recently dividing neutrophils from bone marrow and greater in-group variability of neutrophil kinetics based on in vivo BrdU labeling in a group of older rhesus macaques of 20-26 yr of age. Comparing neutrophil numbers and circulating cytokine levels in rhesus macaques spanning 2 to 26 yr of age, we found a negative correlation between age and blood neutrophil counts and a positive correlation between age and plasma G-CSF levels. Hierarchic clustering analysis also identified strong associations between G-CSF with the proinflammatory cytokines, IL-1β and MIP-1α. Furthermore, neutrophils from older macaques expressed less myeloperoxidase and comprised higher frequencies of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) compared to the young adult macaques. In summary, we observed an earlier release from bone marrow and a reduced production of neutrophils despite the increased levels of plasma G-CSF, especially in the elderly rhesus macaques. This lower neutrophil production capacity associated with increased production of proinflammatory cytokines as well as an earlier release of less mature neutrophils and PMN-MDSCs may contribute to the chronic inflammation and greater susceptibility to infectious and noninfectious diseases during aging.

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Regulation of steady-state neutrophil homeostasis by macrophages

Abstract: The timely clearance of apoptotic neutrophils from inflammation sites is an important function of macrophages; however, the role of macrophages in maintaining neutrophil homeostasis under steadystate conditions is less well understood.

Cited by 95 publications

References 35 publications

Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

Cellular FLIP Inhibits Myeloid Cell Activation by Suppressing Selective Innate Signaling

Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas‐Induced Apoptosis–Transgenic Mice

Declining neutrophil production despite increasing G-CSF levels is associated with chronic inflammation in elderly rhesus macaques

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