The Colony Stimulating Factor-1 Receptor (CSF-1R)-Mediated Regulation of Microglia/Macrophages as a Target for Neurological Disorders (Glioma, Stroke)

Barca, Cristina; Foray, Claudia; Hermann, Sven; Herrlinger, Ulrich; Remory, Isabel; Laoui, Damya; Schäfers, Michael; Grauer, Oliver; Zinnhardt, Bastian

doi:10.3389/fimmu.2021.787307

Cited by 32 publications

(25 citation statements)

References 104 publications

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“…1 ). The CSF1, under physiological conditions, plays a role in cell survival, proliferation, differentiation, and functions of the mononuclear cells, and therefore its higher expression in patients without cancer is not surprising [ 32 – 34 ]. Additionally, peripheral blood mononuclear cells (PBMCs) isolated from the blood of healthy individuals and patients with primary (Gleason 6), mid (Gleeson 7), or distant metastasis (Gleason 9) PCa ( n = 2 per condition) showed that both CSF1 and NOS3 were significantly increased ( p < 0.05) in high-grade PCa patients (Fig.…”

Section: Resultsmentioning

confidence: 99%

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer

et al. 2022

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Sustained oxidative stress in castration-resistant prostate cancer (CRPC) cells potentiates the overall tumor microenvironment (TME). Targeting the TME using colony-stimulating factor 1 receptor (CSF1R) inhibition is a promising therapy for CRPC. However, the therapeutic response to sustained CSF1R inhibition (CSF1Ri) is limited as a monotherapy. We hypothesized that one of the underlying causes for the reduced efficacy of CSF1Ri and increased oxidation in CRPC is the upregulation and uncoupling of endothelial nitric oxide synthase (NOS3). Here we show that in high-grade PCa human specimens, NOS3 abundance positively correlates with CSF1-CSF1R signaling and remains uncoupled. The uncoupling diminishes NOS3 generation of sufficient nitric oxide (NO) required for S-nitrosylation of CSF1R at specific cysteine sites (Cys 224, Cys 278, and Cys 830). Exogenous S-nitrosothiol administration (with S-nitrosoglutathione (GSNO)) induces S-nitrosylation of CSF1R and rescues the excess oxidation in tumor regions, in turn suppressing the tumor-promoting cytokines which are ineffectively suppressed by CSF1R blockade. Together these results suggest that NO administration could act as an effective combinatorial partner with CSF1R blockade against CRPC. In this context, we further show that exogenous NO treatment with GSNOR successfully augments the anti-tumor ability of CSF1Ri to effectively reduce the overall tumor burden, decreases the intratumoral percentage of anti-inflammatory macrophages, myeloid-derived progenitor cells and increases the percentage of pro-inflammatory macrophages, cytotoxic T lymphocytes, and effector T cells, respectively. Together, these findings support the concept that the NO-CSF1Ri combination has the potential to act as a therapeutic agent that restores control over TME, which in turn could improve the outcomes of PCa patients.

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Section: Resultsmentioning

confidence: 99%

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer

et al. 2022

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“…Reproduced by permission of Smith et al 77 and Prest et al 87 kinase present on the surface of macrophages, microglia, and monocyte receptors. 84 The CSF1/CSF1R axis is associated with the proliferation, differentiation, and function of macrophages. PLX3397, a CSF1R inhibitor, reduces the number of macrophage and microglia.…”

Section: Gels/scaffolds That Deliver Signaling Moleculesmentioning

confidence: 99%

Biomaterials delivery strategies to repair spinal cord injury by modulating macrophage phenotypes

et al. 2022

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Spinal cord injury (SCI) causes tremendous harm to a patient’s physical, mental, and financial health. Moreover, recovery of SCI is affected by many factors, inflammation is one of the most important as it engulfs necrotic tissue and cells during the early stages of injury. However, excessive inflammation is not conducive to damage repair. Macrophages are classified into either blood-derived macrophages or resident microglia based on their origin, their effects on SCI being two-sided. Microglia first activate and recruit blood-derived macrophages at the site of injury—blood-borne macrophages being divided into pro-inflammatory M1 phenotypes and anti-inflammatory M2 phenotypes. Among them, M1 macrophages secrete inflammatory factors such as interleukin-β (IL-β), tumor necrosis factor-α (TNF-α), IL-6, and interferon-γ (IFN-γ) at the injury site, which aggravates SCIs. M2 macrophages secrete IL-4, IL-10, IL-13, and neurotrophic factors to inhibit the inflammatory response and inhibit neuronal apoptosis. Consequently, modulating phenotypic differentiation of macrophages appears to be a meaningful therapeutic target for the treatment of SCI. Biomaterials are widely used in regenerative medicine and tissue engineering due to their targeting and bio-histocompatibility. In this review, we describe the effects of biomaterials applied to modulate macrophage phenotypes on SCI recovery and provide an outlook.

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“…CSF-1R-positive macrophages correlate with poor prognosis in various solid cancers [ 102 ]. Targeting CSF-1R can effectively reduce the number of GAMs in the TME and promote GAM repolarization, thus promoting the activation of cytotoxic T-cells, inhibiting tumor growth, and preventing glioblastoma recurrence [ 103 , 104 , 105 , 106 , 107 , 108 ]. The small molecule inhibitor PLX-3397 was assessed in recurrent glioblastoma in a phase II clinical trial.…”

Section: Gam-targeted Therapy In Gbmmentioning

confidence: 99%

Macrophages in Glioblastoma Development and Therapy: A Double-Edged Sword

Shi

Zhu

et al. 2022

Life

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Glioblastoma (GBM) is one of the leading lethal tumors, featuring aggressive malignancy and poor outcome to current standard temozolomide (TMZ) or radio-based therapy. Developing immunotherapies, especially immune checkpoint inhibitors, have improved patient outcomes in other solid tumors but remain fatigued in GBM patients. Emerging evidence has shown that GBM-associated macrophages (GAMs), comprising brain-resident microglia and bone marrow-derived macrophages, act critically in boosting tumor progression, altering drug resistance, and establishing an immunosuppressive environment. Based on its crucial role, evaluations of the safety and efficacy of GAM-targeted therapy are ongoing, with promising (pre)clinical evidence updated. In this review, we summarized updated literature related to GAM nature, the interplay between GAMs and GBM cells, and GAM-targeted therapeutic strategies.

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The Colony Stimulating Factor-1 Receptor (CSF-1R)-Mediated Regulation of Microglia/Macrophages as a Target for Neurological Disorders (Glioma, Stroke)

Cited by 32 publications

References 104 publications

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer

S-nitrosylation of CSF1 receptor increases the efficacy of CSF1R blockage against prostate cancer

Biomaterials delivery strategies to repair spinal cord injury by modulating macrophage phenotypes

Macrophages in Glioblastoma Development and Therapy: A Double-Edged Sword

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