Targeting Macrophages as a Potential Therapeutic Intervention: Impact on Inflammatory Diseases and Cancer

Ponzoni, Mirco; Pastorino, Fabio; Paolo, Daniela Di; Perri, Patrizia; Brignole, Chiara

doi:10.3390/ijms19071953

Cited by 120 publications

(103 citation statements)

References 96 publications

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“…The importance of a temporally dynamic immune response has been highlighted by recent findings that long term resolution of inflammation depends on a sufficiently pro-inflammatory initial response followed by anti-inflammatory and resolving activity 16 . Early pro-inflammatory macrophage response enables clearance of pathogens and damaged cells and subsequently triggers the anti-inflammatory and pro-regenerative response 21,22,45 . Thus, in the current study, we sought to model and control macrophage pro-inflammatory activity, measured by iNOS expression.…”

Section: Discussionmentioning

confidence: 99%

Experimental control of macrophage pro-inflammatory dynamics using predictive models

Weinstock

Forsmo

Wilkinson

et al. 2019

Preprint

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Macrophage activity is a major component of the healthy response to infection and injury that consists of tightly regulated early pro-inflammatory activation followed by anti-inflammatory and regenerative activity. In numerous diseases, however, macrophage polarization becomes dysregulated and can not only impair recovery, but can also promote further injury and pathogenesis, e.g. after injury, in diabetes, or in Alzheimer's disease. Dysregulated macrophages may either fail to polarize or become chronically polarized, resulting in increased production of cytotoxic factors, diminished capacity to clear pathogens, or failure to promote tissue regeneration.In these cases, a method of predicting and dynamically controlling macrophage polarization will enable a new strategy for treating diverse inflammatory diseases. In this work, we developed a model-predictive control framework to temporally regulate macrophage polarization. Using RAW 264.7 macrophages as a model system, we enabled temporal control by identifying transfer function models relating the polarization marker iNOS to exogenous pro-and anti-inflammatory stimuli. These stimuli-to-iNOS response models were identified using linear autoregressive with exogenous input terms (ARX) equations and were coupled with nonlinear elements to account for experimentally identified supra-additive and hysteretic effects. Using this model architecture, we were able to reproduce experimentally observed temporal iNOS dynamics induced with lipopolysaccharides (LPS) and interferon gamma (IFN-γ). Moreover, the identified model enabled the design of time-varying input trajectories to experimentally sustain the duration and magnitude of iNOS expression. By designing transfer function models with the intent to predict cell behavior, we were able to predict and experimentally obtain temporal regulation of iNOS expression using LPS and IFN-γ from both naïve and non-naïve initial states. Moreover, our data driven models revealed decaying magnitude of iNOS response to LPS stimulation over time that could be recovered using combined treatment with both LPS and IFN-. Given the importance of dynamic tissue macrophage polarization and overall inflammatory regulation to a broad number of diseases, the temporal control methodology presented here will have numerous applications for regulating immune activity dynamics in chronic inflammatory diseases.3

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Section: Discussionmentioning

confidence: 99%

Experimental control of macrophage pro-inflammatory dynamics using predictive models

Weinstock

Forsmo

Wilkinson

et al. 2019

Preprint

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“…Liposomes are considered to be among the most successful drug delivery systems developed, with several formulations in clinical trials or on the market . Liposomes without surface shielding are inherently recognized by MPS cells, and alterations to their physicochemical properties can further improve uptake by monocytes and macrophages.…”

Section: Synthetic Biomaterials To Target Tams In Cancer By Systemic mentioning

confidence: 99%

“…Liposomal formulations of bisphosphonates (e.g., clodronate and alendronate), compounds that induce apoptosis upon internalization, are used as agents for macrophage depletion in animal models . In a murine teratocarcinoma and human rhabdomyosarcoma model, liposomal clodronate effectively depleted monocytes and macrophages, suppressing tumor growth and angiogenesis by up to 92% .…”

Section: Synthetic Biomaterials To Target Tams In Cancer By Systemic mentioning

confidence: 99%

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Progress on Modulating Tumor‐Associated Macrophages with Biomaterials

2019

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Tumor‐associated macrophages (TAMs) are a complex and heterogeneous population of cells within the tumor microenvironment. In many tumor types, TAMs contribute toward tumor malignancy and are therefore a therapeutic target of interest. Here, three major strategies for regulating TAMs are highlighted, emphasizing the role of biomaterials in these approaches. First, systemic methods for targeting tumor‐associated macrophage are summarized and limitations to both passive and active targeting approaches considered. Second, lessons learned from the significant literature on wound healing and macrophage response to implanted biomaterials are discussed with the vision of applying these principles to localized, biomaterial‐based modulation of tumor‐associated macrophage. Finally, the developing field of engineered macrophages, including genetic engineering and integration with biomaterials or drug delivery systems, is examined. Analysis of major challenges in the field along with exciting opportunities for the future of macrophage‐based therapies in oncology are included.

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“…Macrophages are components of the innate immune system that play essential roles in various biological processes, including clearance of infectious agents, dead cells, and foreign materials as well as cytokine production, antigen presentation, and tissue repair (Kierdorf, Prinz, Geissmann, & Gomez, 2015;Perdiguero & Geissmann, 2016). As the first line of defense against foreign substances, it is probably not surprising that macrophages can often be affected by therapeutic agents through intended (i.e., pharmacological) or sometimes unintended (i.e., off-target, potentially toxicological) effects (Laskin, 2009;Poh & Ernst, 2018;Ponzoni, Pastorino, Di, Perri, & Brignole, 2018). Therefore, evaluating effects of drugs on macrophages is important for drug development at preclinical stages.…”

Section: Introductionmentioning

confidence: 99%

Generation of Macrophages from Cynomolgus‐Monkey Bone Marrow as a Model to Evaluate Effects of Drugs on Innate Immunity

Ludmann

Anest

et al. 2019

CP Toxicology

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Macrophages are innate immune cells that play important roles in various physiological and pathological processes. Evaluation of pro‐inflammatory effects of drugs on macrophages has become commonplace in preclinical drug development prior to human clinical trials. Despite their body‐wide distribution, tissue macrophages are often difficult to collect from large animals and humans in a noninvasive manner. Therefore, in vitro–differentiated macrophages are important tools to facilitate cross‐species analysis of macrophage function. Although cynomolgus monkeys are an essential non‐rodent species for preclinical research, in vitro differentiation of cynomolgus‐monkey macrophages has been poorly characterized. In the present unit, we describe a protocol to differentiate cynomolgus‐monkey macrophages from isolated bone marrow mononuclear cells (BMMCs). In contrast to monocytes, cynomolgus‐monkey BMMCs show robust expansion in the presence of macrophage colony–stimulating factor in vitro, which allows expansion of many cells from a single animal donor. Macrophages differentiated from BMMCs retain many of the macrophage phenotypes and functions, including phagocytosis and cytokine release, and therefore can be used as a surrogate to assess effects of drugs on cynomolgus‐monkey macrophages. © 2019 by John Wiley & Sons, Inc.

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Targeting Macrophages as a Potential Therapeutic Intervention: Impact on Inflammatory Diseases and Cancer

Cited by 120 publications

References 96 publications

Experimental control of macrophage pro-inflammatory dynamics using predictive models

Experimental control of macrophage pro-inflammatory dynamics using predictive models

Progress on Modulating Tumor‐Associated Macrophages with Biomaterials

Generation of Macrophages from Cynomolgus‐Monkey Bone Marrow as a Model to Evaluate Effects of Drugs on Innate Immunity

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