Neisseria gonorrhoeaeInduces a Tolerogenic Phenotype in Macrophages to Modulate Host Immunity

Abstract

Neisseria gonorrhoeae is the etiological agent of gonorrhoea, which is a sexually transmitted disease widespread throughout the world. N. gonorrhoeae does not improve immune response in patients with reinfection, suggesting that gonococcus displays several mechanisms to evade immune response and survive in the host. N. gonorrhoeae is able to suppress the protective immune response at different levels, such as B and T lymphocytes and dendritic cells. In this study, we determined whether N. gonorrhoeae directly conditions the phenotype of RAW 264.7 murine macrophage cell line and its response. We established that gonococcus was effectively phagocytosed by the RAW 264.7 cells and upregulates production of immunoregulatory cytokines (IL-10 and TGF-β1) but not the production of proinflammatory cytokine TNF-α, indicating that gonococcus induces a shift towards anti-inflammatory cytokine production. Moreover, N. gonorrhoeae did not induce significant upregulation of costimulatory CD86 and MHC class II molecules. We also showed that N. gonorrhoeae infected macrophage cell line fails to elicit proliferative CD4+ response. This implies that macrophage that can phagocytose gonococcus do not display proper antigen-presenting functions. These results indicate that N. gonorrhoeae induces a tolerogenic phenotype in antigen-presenting cells, which seems to be one of the mechanisms to induce evasion of immune response.

Neisseria gonorrhoeaesurvives within and modulates apoptosis and inflammatory cytokine production of human macrophages

“…8), we postulate that M2 macrophages may be the more relevant phenotype within the genital tract. Escobar et al (2013) had previously suggested that cytokines induced by N. gonorrhoeae from RAW 264.7 mouse macrophages correspond to an M2 profile and had recently published that N. gonorrhoeae can polarize Survival, apoptosis and cytokine modulation by Neisseria gonorrhoeae in human macrophages 555 human macrophages to an M2 profile (Ortiz et al, 2015). The phenotype of macrophages in the genital tract of patients will have to be investigated to determine whether there is polarization during natural gonococcal infection.…”

“…The secretion of TNF-α and GM-CSF can also contribute to prolong the life of PMNs. The secretion of the regulatory cytokine IL-10 can have a potent T-cell suppressive function (Escobar et al, 2013), and it has been previously shown that N. gonorrhoeae suppresses T-cell function (Boulton and Gray-Owen, 2002;Lee et al, 2008;Zhu et al, 2012) and may induce a localized immune suppression (Liu et al, 2014). IL-6 and TNF-α may also trigger the influx of lymphocytes.…”

Neisseria gonorrhoeae Modulates Immunity by Polarizing Human Macrophages to a M2 Profile

“…gonorrhoeae potently inhibits the ability of antigen-primed bone-marrow-derived DCs (BMDC) to trigger T-cell proliferation by inducing expression of both immunosuppressive cytokines and tolerance-inducing cell surface protein [ 14 ]. Furthermore Escobar et al [ 15 ] recently demonstrated that GC modulates MΦ and their functionality, producing a shift towards anti-inflammatory cytokine production, inefficient upregulation in molecules involved in antigen presentation and T-cell activation and a poor allogeneic T-cell stimulatory activity [ 15 ]. These studies showed that N .…”

“…Although N . gonorrhoeae has been reported to modulate MΦ [ 15 , 23 ], GC influence on MΦ polarization has not been yet explored. In order to address this issue we studied the effect of N .…”

Could Vaccination Against Neisseria Gonorrhoeae be on the Horizon?

“…The first of these, is the recent findings that N. gonorrhoeae proactively manipulates the host immune response for its own benefit, by selectively eliciting innate host defenses that it can survive while concomitantly suppressing adaptive immune responses that would eliminate it [11]. Several mechanisms have been described that contribute to this ability, including inactivation of T-helper cells [12], modulation of dendritic cells or macrophages [13,14] and upregulation of IL-10, TGF-β and type 1 regulatory T cells [15]. These findings reveal new understandings of immunity to N. gonorrhoeae and suggest that novel approaches to reverse gonococcus-induced immunosuppression might be fruitful; moreover they inform new strategies for vaccine development.…”