Natural Killer Cells Regulate Pulmonary Macrophages Polarization in Host Defense Against Chlamydial Respiratory Infection

Abstract

NK cells and pulmonary macrophages both are important components of innate immunity. The interaction between NK cells and pulmonary macrophages during chlamydial infection is poorly understood. In this study, we explored the effect of NK cells on regulation of pulmonary macrophage function during chlamydial respiratory infection. We found that NK depletion led to polarization of pulmonary macrophages from M1 to M2 phenotype, and it is related to reduced miR-155 expression in lung macrophage. Using adoptive transfer approach, we found that the recipients receiving lung macrophages isolated from C. muridarum-infected NK-cell-depleted mice exhibited an increased bacterial load and severe inflammation in the lung upon chlamydial challenge infection when compared with the recipients of lung macrophages from infected isotype control antibody treated mice. Herein, the effects of NK cells on macrophage polarization were examined in vitro. We found that NK cells from chlamydial-infected mice (iNK) significantly induced M1 polarization compared to that from uninfected mice (uNK). Inhibition of miR-155 expression in macrophages reduced M1 polarization induced by iNK, while miR-155 over-expression enhanced it. Furthermore, neutralization of IFN-γ in the coculture system decreased the expression of miR-155 by macrophages, and resulted in weakened M1 polarization. The data indicates that NK cells promote M1 polarization through up-regulation of miR-155 in macrophages by producing IFN-γ during chlamydial infection, and NK-regulated macrophage polarization is functionally relevant to host defense against the infection.

Chlamydia muridarum infection causes bronchointerstitial pneumonia in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice

“…25 Furthermore, NK cell depletion in mice alters pulmonary macrophage polarization from an M1 to M2 phenotype, which in turn results in higher bacterial loads and more severe pulmonary inflammation than controls during Cm infection. 28 Interestingly, the first 11 mice in our experiment developed clinical disease including dyspnea, lethargy, hunched posture, and weight loss, but the subsequent 8 NSGs infected at a later timepoint had minimal to no clinical signs, even though the majority possessed pulmonary lesions. A cause for this is uncertain although it could be related to differences in the infectious dose shed by the donor mice or present in dirty bedding material used in the 2 separate cohousing experiments (November/December vs April/May) or differences in the virulence of the field Cm strains infecting the lungs of NSG mice for each experiment.…”

Cross Talk Between Natural Killer T and Dendritic Cells and Its Impact on T Cell Responses in Infections

“…Notably, the influence of NK cells could reach multiple cell types. For example, we recently found NK cells can influence macrophage polarization in the lung following chlamydial infection (71). Similarly, the newly reported molecules such as SND1 and Sema3E, which modulate DC functions in infections (72,73), would be an area for exploring the molecular mechanisms related to the modulating effect of NKT and NK cells on DC function infections.…”

A Pathogenic Role for FcγRI in the Immune Response against Chlamydial Respiratory Infection

“…These data indicated that FcγRI might limit the infiltration and activation of NK cells in chlamydial infection. In the studies of chlamydial respiratory infection, NK cells were primarily defined to play important regulatory roles on other immune cells, such as DCs, Th1/Th17 cells, and macrophages [ 27 , 28 , 29 ], instead of directly killing the pathogen. Combined with the identified FcγRI’s impact on macrophages and Th1 response in this study, we believed that the FcγRI-regulated NK-macrophage interaction or NK-Th1 interaction will provide a promising direction for further mechanistic exploration.…”