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

Abstract

Current data suggest that Neisseria gonorrhoeae is able to suppress the protective immune response at different levels, such as B and T lymphocytes and antigen-presenting cells. The present report is focused on gonococcus evasion mechanism on macrophages (MФ) and its impact in the subsequent immune response. In response to various signals MФ may undergo classical-M1 (M1-MФ) or alternative-M2 (M2-MФ) activation. Until now there are no reports of the gonococcus effects on human MФ polarization. We assessed the phagocytic ability of monocyte-derived MФ (MDM) upon gonococcal infection by immunofluorescence and gentamicin protection experiments. Then, we evaluated cytokine profile and M1/M2 specific-surface markers on MФ challenged with N. gonorrhoeae and their proliferative effect on T cells. Our findings lead us to suggest N. gonorrhoeae stimulates a M2-MФ phenotype in which some of the M2b and none of the M1-MФ-associated markers are induced. Interestingly, N. gonorrhoeae exposure leads to upregulation of a Programmed Death Ligand 1 (PD-L1), widely known as an immunosuppressive molecule. Moreover, functional results showed that N. gonorrhoeae-treated MФ are unable to induce proliferation of human T-cells, suggesting a more likely regulatory phenotype. Taken together, our data show that N. gonorroheae interferes with MФ polarization. This study has important implications for understanding the mechanisms of clearance versus long-term persistence of N. gonorroheae infection and might be applicable for the development of new therapeutic strategies.

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.…”

M2b macrophage polarization and its roles in diseases

“…In activated macrophages, M1 and M2b are the main cell types expressing and secreting TNF‐α . Accumulating evidences have shown that TNF‐α, in combination with other markers, such as IL‐10, LIGHT, CCL1, or/and IL‐6, can discriminate M2b from the other subtypes of macrophages very well . In addition, TNF‐α is considered a marker of M2b macrophages in many review articles …”

“…IL‐6 is highly expressed in M1 and M2b macrophages but not in M2a and M2c . Growing data show that in combination with other markers (IL‐10, LIGHT, CCL1, or/and TNF‐α), IL‐6 can identify M2b from the other macrophage subsets …”

“…75 Accumulating evidences have shown that TNF-, in combination with other markers, such as IL-10, LIGHT, CCL1, or/and IL-6, can discriminate M2b from the other subtypes of macrophages very well. 30,71,[75][76][77][78][79][80] In addition, TNF-is considered a marker of M2b macrophages in many review articles. 6,8,9,11,41,62,63…”

“…71,78 Growing data show that in combination with other markers (IL-10, LIGHT, CCL1, or/and TNF-), IL-6 can identify M2b from the other macrophage subsets. 30,71,[77][78][79][80][88][89][90] In addition to the above molecules, other molecules used to identify M2b macrophages include MHCII/HLA-DR, CD163, CD64, PD-L1 IL-1 , and CCL2. 26,27,30,75,[91][92][93] However, these molecules are not specific markers of M2b, nor even specific markers of macrophages.…”