Tumour cell conditioned medium reveals greater M2 skewing of macrophages in the absence of properdin

Al-Rayahi, Izzat; Browning, Michael; Stover, Cordula M.

doi:10.1002/iid3.142

Cited by 13 publications

(9 citation statements)

References 35 publications

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“…These observations are similar to what has been observed previously with factor H ( 19 ), which is intriguing, since properdin and factor H have opposing effects on the regulation of complement activation ( 3 ). These findings were also consistent with previous reports, which have demonstrated that properdin deficient mice have a reduced M1 (IL-1β) and increased M2 (arginase-1, MCP-1, IL-10) profile, crucial for the tumor microenvironment ( 31 ). This suggests that the production of IL-1β and reduction in IL-10 mediated by properdin may be required for protection against M. tuberculosis in the initial phase of infection.…”

Section: Discussionsupporting

confidence: 93%

Human Properdin Modulates Macrophage: Mycobacterium bovis BCG Interaction via Thrombospondin Repeats 4 and 5

et al. 2018

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Mycobacterium tuberculosis can proficiently enter macrophages and diminish complement activation on its cell surface. Within macrophages, the mycobacterium can suppress macrophage apoptosis and survive within the intracellular environment. Previously, we have shown that complement regulatory proteins such as factor H may interfere with pathogen–macrophage interactions during tuberculosis infection. In this study, we show that Mycobacterium bovis BCG binds properdin, an upregulator of the complement alternative pathway. TSR4+5, a recombinant form of thrombospondin repeats 4 and 5 of human properdin expressed in tandem, which is an inhibitor of the alternative pathway, was also able to bind to M. bovis BCG. Properdin and TSR4+5 were found to inhibit uptake of M. bovis BCG by THP-1 macrophage cells in a dose-dependent manner. Quantitative real-time PCR revealed elevated pro-inflammatory responses (TNF-α, IL-1β, and IL-6) in the presence of properdin or TSR4+5, which gradually decreased over 6 h. Correspondingly, anti-inflammatory responses (IL-10 and TGF-β) showed suppressed levels of expression in the presence of properdin, which gradually increased over 6 h. Multiplex cytokine array analysis also revealed that properdin and TSR4+5 significantly enhanced the pro-inflammatory response (TNF-α, IL-1β, and IL-1α) at 24 h, which declined at 48 h, whereas the anti-inflammatory response (IL-10) was suppressed. Our results suggest that properdin may interfere with mycobacterial entry into macrophages via TSR4 and TSR5, particularly during the initial stages of infection, thus affecting the extracellular survival of the pathogen. This study offers novel insights into the non-complement related functions of properdin during host–pathogen interactions in tuberculosis.

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Section: Discussionsupporting

confidence: 93%

Human Properdin Modulates Macrophage: Mycobacterium bovis BCG Interaction via Thrombospondin Repeats 4 and 5

et al. 2018

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“…Given a positive correlation with immune infiltration, the properdin expression levels reflect the presence of immune cells that are less immunosuppressive but can engage in the anti-tumor response. Another possibility is that properdin acts as a balancing factor between macrophage polarization between pro-inflammatory M1 and anti-inflammatory M2 phenotypes ( 30 ). NK cells, a key player in the anti-tumor immunity, have recently been shown to bind properdin through NKp46 receptor ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages derived from properdin knockout mice showed a shift to M2 phenotype, with increased type II cellular immune responses and decreased MHC class II expression (30). The lack of properdin has also been shown to protect the host from an aggravated inflammatory response, increasing the survival of properdin gene knock-out mice compared to wild type mice (31)(32)(33)(34).…”

Section: Introductionmentioning

confidence: 99%

Prognostic Value of Complement Properdin in Cancer

Mangogna

Varghese²,

Agostinis³

et al. 2021

Front. Immunol.

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The complement system is readily triggered by the presence of damage-associated molecular patterns on the surface of tumor cells. The complement alternative pathway provides rapid amplification of the molecular stress signal, leading to complement cascade activation to deal with pathogens or malignant cells. Properdin is the only known positive regulator of the alternative pathway. In addition, properdin promotes the phagocytic uptake of apoptotic T cells by macrophages and dendritic cells without activating the complement system, thus, establishing its ability to recognize “altered-self”. Dysregulation of properdin has been implicated in substantial tissue damage in the host, and in some cases, chronic unresolved inflammation. A corollary of this may be the development of cancer. Hence, to establish a correlation between properdin presence/levels in normal and cancer tissues, we performed bioinformatics analysis, using Oncomine and UALCAN. Survival analyses were performed using UALCAN and PROGgeneV2 to assess if properdin can serve as a potential prognostic marker for human lung adenocarcinoma (LUAD), liver hepatocellular carcinoma (LIHC), cervical squamous cell carcinoma (CESC), and pancreatic adenocarcinoma (PAAD). We also analyzed levels of tumor-infiltrating immune cells using TIMER, a tool for characterizing immune cell composition in cancers. We found that in LUAD and LIHC, there was a lower expression of properdin in the tumors compared to normal tissues, while no significant difference was observed in CESC and PAAD. Survival analysis demonstrated a positive association between properdin mRNA expression and overall survival in all 4 types of cancers. TIMER analysis revealed that properdin expression correlated negatively with tumor purity and positively with levels of infiltrating B cells, cytotoxic CD8+ T cells, CD4+ helper T cells, macrophages, neutrophils and dendritic cells in LUAD, CESC and PAAD, and with levels of B cells, CD8+ T cells and dendritic cells in LIHC. Immunohistochemical analysis revealed that infiltrating immune cells were the most likely source of properdin in the tumor microenvironment. Thus, complement protein properdin shows promise as a prognostic marker in cancer and warrants further study.

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“…Tumor cells thrive on an immunosuppressed microenvironment. To this effect, conditioned medium from melanoma B16F10 tumor cells has been shown to prime M1 macrophages, characterized by upregulation of iNOS, IL-1β, TNF-α, IL-12, IL-23, CXCL-9, and CXCL-10 ( 31 ). Thus, the tumor microenvironment could potentially be modulated by properdin-CNTs.…”

Section: Discussionmentioning

confidence: 99%

“…Macrophages of properdin-deficient mice have reduced M1 phenotype (IL-1β) and an increased production in the M2 phenotype (arginase-1, MCP-1, and IL-10) associated with tumour-promoting activity. This suggests that the deficiency in properdin can modulate macrophages toward an M2 phenotype, which enhances the tumor environment ( 31 ).…”

Section: Introductionmentioning

confidence: 99%

Human Properdin Opsonizes Nanoparticles and Triggers a Potent Pro-inflammatory Response by Macrophages without Involving Complement Activation

et al. 2018

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Development of nanoparticles as tissue-specific drug delivery platforms can be considerably influenced by the complement system because of their inherent pro-inflammatory and tumorigenic consequences. The complement activation pathways, and its recognition subcomponents, can modulate clearance of the nanoparticles and subsequent inflammatory response and thus alter the intended translational applications. Here, we report, for the first time, that human properdin, an upregulator of the complement alternative pathway, can opsonize functionalized carbon nanotubes (CNTs) via its thrombospondin type I repeat (TSR) 4 and 5. Binding of properdin and TSR4+5 is likely to involve charge pattern/polarity recognition of the CNT surface since both carboxymethyl cellulose-coated carbon nanotubes (CMC-CNT) and oxidized (Ox-CNT) bound these proteins well. Properdin enhanced the uptake of CMC-CNTs by a macrophage cell line, THP-1, mounting a robust pro-inflammatory immune response, as revealed by qRT-PCR, multiplex cytokine array, and NF-κB nuclear translocation analyses. Properdin can be locally synthesized by immune cells in an inflammatory microenvironment, and thus, its interaction with nanoparticles is of considerable importance. In addition, recombinant TSR4+5 coated on the CMC-CNTs inhibited complement consumption by CMC-CNTs, suggesting that nanoparticle decoration with TSR4+5, can be potentially used as a complement inhibitor in a number of pathological contexts arising due to exaggerated complement activation.

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Tumour cell conditioned medium reveals greater M2 skewing of macrophages in the absence of properdin

Cited by 13 publications

References 35 publications

Human Properdin Modulates Macrophage: Mycobacterium bovis BCG Interaction via Thrombospondin Repeats 4 and 5

Human Properdin Modulates Macrophage: Mycobacterium bovis BCG Interaction via Thrombospondin Repeats 4 and 5

Prognostic Value of Complement Properdin in Cancer

Human Properdin Opsonizes Nanoparticles and Triggers a Potent Pro-inflammatory Response by Macrophages without Involving Complement Activation

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