G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

Bajrami, Besnik; Zhu, Haiyan; Kwak, Hyun-Jeong; Mondal, Subhanjan; Hou, Qingming; Geng, Guangfeng; Karatepe, Kutay; Zhang, Yu C.; Nombela‐Arrieta, César; Park, Shin-Young; Loison, Fabien; Sakai, Jiro; Xu, Yuanfu; Silberstein, Leslie E.; Luo, Hongbo

doi:10.1084/jem.20160393

Cited by 78 publications

(59 citation statements)

References 80 publications

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“…4B, C and not shown). Notably, as previously reported in different models [45][46][47] , blocking G-CSF did not alter monocyte numbers in the kidney (Fig. 4D).…”

Section: Neutrophils Are Responsible For Kidney Inflammation After Sksupporting

confidence: 87%

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Skopelja-Gardner

Tai

Sun

et al. 2020

Preprint

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Photosensitivity to ultraviolet (UV) light affects up to ~80% of lupus patients and can exacerbate local skin disease as well as systemic disease, including lupus nephritis. While neutrophils have been implicated in local tissue injury in lupus in response to immune complex deposition, whether and how they play a role in photosensitivity induced systemic disease is unknown. Here, we show that following skin exposure to UV light, neutrophils migrate not only to the skin, but also to the kidney, in an IL-17A-dependent manner. Kidney infiltrating neutrophils produced reactive oxygen species and their presence was associated with upregulation of endothelial adhesion molecules and inflammatory cytokines as well as the induction of kidney injury markers, including transient proteinuria. Neutrophils were responsible for inflammation and renal injury as demonstrated by experiments that inhibited neutrophil mobilization. Exploiting a mouse model containing photoactivatable immune cells, we observed that a subset of neutrophils found in the kidney had transited through UV light-exposed skin suggesting reverse transmigration. These findings demonstrate that neutrophils mediate transient kidney injury following skin exposure to UV light and, coupled with observations identifying similar neutrophil phenotypes in human lupus, could provide a mechanistic link to explain sun-induced systemic lupus flares.

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“…4B, C and not shown). Notably, as previously reported in different models [45][46][47] , blocking G-CSF did not alter monocyte numbers in the kidney (Fig. 4D).…”

Section: Neutrophils Are Responsible For Kidney Inflammation After Sksupporting

confidence: 87%

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Skopelja-Gardner

Tai

Sun

et al. 2020

Preprint

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“…IL-1 is known to be protective early during Mtb infection while exacerbating pathology during later infection, highlighting that the effects of IL-1 on adaptive immunity are complex and likely dependent on the host and infection model. G-CSF was increased in granulomas from LZD+IL-1Rn treated macaques which, combined with our observations of reduced PMN infiltrates in mouse lungs and macaque airways, indicated a paradoxical role of G-CSF as a neutrophil production and differentiation factor (30). However, in a model of LPS-induced lung injury it was shown that G-CSF blockade induced accumulation of PMNs and increased inflammation in the lungs, indicating pulmonary inflammation may not follow dogmatic rules of canonical inflammatory pathways (30).…”

Section: Discussionsupporting

confidence: 64%

Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

Winchell

Mishra

Phuah

et al. 2019

Preprint

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AbstractIn 2017 over 550,000 estimated new cases of multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) occurred, emphasizing a need for new treatment strategies. Linezolid (LZD) is a potent antibiotic for drug-resistant Gram-positive infections and is an effective treatment for TB. However, extended LZD use can lead to LZD-associated host toxicities, most commonly bone marrow suppression. LZD toxicities may be mediated by IL-1, an inflammatory pathway important for early immunity during M. tuberculosis infection. However, IL-1 can contribute to pathology and disease severity late in TB progression. Since IL-1 may contribute to LZD toxicity and does influence TB pathology, we targeted this pathway with a potential host-directed therapy (HDT). We hypothesized LZD efficacy could be enhanced by modulation of IL-1 pathway to reduce bone marrow toxicity and TB associated-inflammation. We used two animal models of TB to test our hypothesis, a TB-susceptible mouse model and clinically relevant cynomolgus macaques. Antagonizing IL-1 in mice with established infection reduced lung neutrophil numbers and partially restored the erythroid progenitor populations that are depleted by LZD. In macaques, we found no conclusive evidence of bone marrow suppression associated with LZD, indicating our treatment time may have been short enough to avoid the toxicities observed in humans. Though treatment was only 4 weeks (the FDA approved regimen at the time of study), we observed sterilization of the majority of granulomas regardless of co-administration of the FDA-approved IL-1 receptor antagonist (IL-1Rn), also known as Anakinra. However total lung inflammation was significantly reduced in macaques treated with IL-1Rn and LZD compared to LZD alone. Importantly, IL-1Rn administration did not impair the host response against Mtb or LZD efficacy in either animal model. Together, our data support that inhibition of IL-1 in combination with LZD has potential to be an effective HDT for TB and the need for further research in this area.

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“…Anti-G-CSF antibodies alone increased LPS-induced BAL neutrophil numbers and G-CSF levels, which has been reported to be due to the ability of anti-G-CSF antibodies to disinhibit CXCR2 signaling [27]. In addition, anti-G-CSF antibodies alone did not inhibit TNF or IL-6, which both contribute to the rise of BAL neutrophils [28, 29].…”

Section: Resultsmentioning

confidence: 99%

Granulocyte colony-stimulating factor blockade enables dexamethasone to inhibit lipopolysaccharide-induced murine lung neutrophils

et al. 2017

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Glucocorticoids promote neutrophilic inflammation, the mechanisms of which are poorly characterized. Using a lipopolysaccharide (LPS)-induced acute murine lung injury model, we determined the role of granulocyte colony-stimulating factor (G-CSF) in mouse lung neutrophil numbers in the absence and presence of dexamethasone, a potent glucocorticoid. G-CSF was blocked using a neutralizing antibody. Airway neutrophil numbers, cytokine levels, and lung injury parameters were measured. Glucocorticoid treatment maintained LPS-induced airway G-CSF while suppressing TNF and IL-6. The addition of anti-G-CSF antibodies enabled dexamethasone to decrease airway G-CSF, neutrophils, and lung injury scores. In LPS-challenged murine lungs, structural cells and infiltrating leukocytes produced G-CSF. In vitro using BEAS 2B bronchial epithelial cells, A549 lung epithelial cells, human monocyte-derived macrophages, and human neutrophils, we found that dexamethasone and proinflammatory cytokines synergistically induced G-CSF. Blocking G-CSF production in BEAS 2B cells using shRNAs diminished the ability of BEAS 2B cells to protect neutrophils from undergoing spontaneous apoptosis. These data support that G-CSF plays a role in upregulation of airway neutrophil numbers by dexamethasone in the LPS-induced acute lung injury model.

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G-CSF maintains controlled neutrophil mobilization during acute inflammation by negatively regulating CXCR2 signaling

Abstract: Luo et al. report that CXCR2 ligands are responsible for rapid neutrophil mobilization during early-stage acute inflammation and that G-CSF suppresses this mobilization by negatively regulating CXCR2-mediated intracellular signaling.

Cited by 78 publications

References 80 publications

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Neutrophils Mediate Kidney Inflammation Following Acute Skin Exposure to UVB Light

Evaluation of IL-1 blockade as an adjunct to linezolid therapy for tuberculosis in mice and macaques

Granulocyte colony-stimulating factor blockade enables dexamethasone to inhibit lipopolysaccharide-induced murine lung neutrophils

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