Macrophage M1/M2 Polarization Dynamically Adapts to Changes in Cytokine Microenvironments in Cryptococcus neoformans Infection

Abstract

The outcome of cryptococcal pneumonia correlates with local macrophage polarization status, as M1 and M2 polarization marks protective and nonprotective responses, respectively. Overall, pulmonary macrophage polarization status changes over time during a cryptococcal infection. This could have been caused by repolarization of individual macrophages or by a replacement of M2-polarized cells by new M1-polarized cells. To explore the ability of macrophages to change between polarization states, we conducted a series of experiments using in vitro macrophages. Coculture of macrophages with Cryptococcus neoformans resulted in development of a weak M1-like phenotype, with modestly increased inducible nitric oxide synthase (iNOS) but lacking interleukin 6 (IL-6) induction. The C. neoformans-induced M1-like polarization state was plastic, as macrophages stimulated first with C. neoformans and then with gamma interferon (IFN-γ) or IL-4 expressed mRNA polarization patterns similar to those stimulated with cytokines alone. To further evaluate macrophage polarization plasticity, cytokine stimulatory conditions were established which fully polarized macrophages. IFN-γ and IL-4 stimulation differentially induced complete M1 and M2 polarization, defined by differential expression of marker mRNA panels, surface marker expression, and tumor necrosis factor alpha (TNF-α) protein production. Switching IFN-γ- to IL-4-stimulating conditions, and vice versa, resulted in uniform changes in profiles of polarization marker genes consistent with the most recent cytokine environment. Furthermore, the ability of sequentially stimulated macrophages to inhibit C. neoformans reflected the most recent polarizing condition, independent of previous polarization. Collectively, these data indicate that M1/M2 macrophage polarization phenotypes are highly plastic to external signals, and interventions which therapeutically repolarize macrophages could be beneficial for treatment of cryptococcosis.

Differential Macrophage Polarization from Pneumocystis in Immunocompetent and Immunosuppressed Hosts: Potential Adjunctive Therapy during Pneumonia

“…Together, these data clearly support the contribution of an alternatively activated M2 response with elevated Dectin-1 levels as effective macrophage host defense promoting the clearance of Pneumocystis. In addition, our study further supports that P. carinii-induced macrophage polarization can completely be reversed at both the levels of gene and protein expression levels if the macrophage is provided with appropriate cytokine stimuli, a finding consistent with other models (32).…”

“…Macrophages offer a novel approach to cell therapy in the treatment of infection, especially in the immunosuppressed hosts, but require additional investigation (26)(27)(28)(29)(30)(31). There are relatively few reports concerning macrophage polarization and the resulting antifungal and anti-inflammatory activity as a potential treatment approach for fungal infections (12,32,33).…”

Treatment with Recombinant Trichinella spiralis Cathepsin B–like Protein Ameliorates Intestinal Ischemia/Reperfusion Injury in Mice by Promoting a Switch from M1 to M2 Macrophages

“…Studies showed that M1 macrophages were induced in Th1 microenvironment and M2 macrophages were induced in Th2 microenvironment (34). Therefore, to elucidate the effect of intestinal I/R and rTsCPB on macrophage switch, we determined the mRNA and protein levels of M1 markers (NOS2 and CCR7) and M2 markers (Arg-1 and Fizz1) in the intestine.…”

Assessing the Impact of BCG Vaccine and Fertile Hydatid Cyst Fluid in Classical and Alternative Macrophage Polarization

“…Davis et al (2013) studied the expression of IFNγ and INOS in infection of Cryptococcus neoformance to investigate the polarization of M1 and M2 macrophages. They used ELISA, flow cytometry, Real-Time PCR and immune florescence during their experiment (Davis et al, 2013).…”

“…Davis et al (2013) studied the expression of IFNγ and INOS in infection of Cryptococcus neoformance to investigate the polarization of M1 and M2 macrophages. They used ELISA, flow cytometry, Real-Time PCR and immune florescence during their experiment (Davis et al, 2013). Martinez and Gordon (2014) evaluated the amount of M1 and they increased the amount of M2 macrophages in rat spinal cord injuries which can play a role in tissue repair (Kigerl et al, 2009).…”