Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

Abstract

Pseudomonas aeruginosa persists in patients with cystic fibrosis (CF) and drives CF lung disease progression. P. aeruginosa potently activates the innate immune system, mainly mediated through pathogen-associated molecular patterns, such as flagellin. However, the host is unable to eradicate this flagellated bacterium efficiently. The underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells generated in cancer and proinflammatory microenvironments and are capable of suppressing T cell responses. We hypothesized that P. aeruginosa induces MDSCs to escape T cell immunity. In this article, we demonstrate that granulocytic MDSCs accumulate in CF patients chronically infected with P. aeruginosa and correlate with CF lung disease activity. Flagellated P. aeruginosa culture supernatants induced the generation of MDSCs, an effect that was 1) dose-dependently mimicked by purified flagellin protein, 2) significantly reduced using flagellin-deficient P. aeruginosa bacteria, and 3) corresponded to TLR5 expression on MDSCs in vitro and in vivo. Both purified flagellin and flagellated P. aeruginosa induced an MDSC phenotype distinct from that of the previously described MDSC-inducing cytokine GM-CSF, characterized by an upregulation of the chemokine receptor CXCR4 on the surface of MDSCs. Functionally, P. aeruginosa–infected CF patient ex vivo–isolated as well as flagellin or P. aeruginosa in vitro–generated MDSCs efficiently suppressed polyclonal T cell proliferation in a dose-dependent manner and modulated Th17 responses. These studies demonstrate that flagellin induces the generation of MDSCs and suggest that P. aeruginosa uses this mechanism to undermine T cell–mediated host defense in CF and other P. aeruginosa–associated chronic lung diseases.

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD

“…When viewed in combination, these markers were suggestive of a granulocytic/neutrophilic MDSC subtype (PMN-MDSCs). 18,29 Percentages of monocytic MDSCs in peripheral blood were substantially lower (monocytic MDSCs mean 0.12% before ECP) compared with PMN-MDSCs (mean 6% before ECP) in our patient cohorts and did not change significantly upon ECP treatment (Supplementary Figure 2). We therefore systematically followed up on the observation that ECP Table 1.…”

Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype

“…Recently, Zhao et al (37) showed an association of an upregulation of CXCL12 and an accumulation of MDSCs in the pregnant mouse uterus. Moreover, GR-MDSCs in CF patients were recently shown to express CXCR4 (16). Because AMD3100 only partially blocked suppressive activity, other mechanisms besides CXCR4 may be involved in MDSC activation.…”

“…1A). plaGR-MDSCs showed the typical morphology of granulocytic cells with a segmented nucleus (12,14,16,22) (Fig. 1B).…”

“…They are part of normal hematopoiesis but are dramatically expanded and activated in many types of cancer in humans and mice (11)(12)(13)(14) as well as under other pathological conditions such as infection (15,16), trauma (17), or transplant rejection (18,19). GR-MDSCs express the common myeloid marker CD33 and the granulocytic lineage markers CD66b or CD15 whereas they do not exhibit monocytic Ags such as CD14 and HLA-DR (10,20,21).…”

Myeloid-derived suppressor cells and myeloid regulatory cells in cancer and autoimmune disorders

“…These findings demonstrate that MDSCs can suppress Th17 response. In another study, MDSCs derived from patients infected with Pseudomonas aeruginosa evidently dampened the IL-17 protein production by CD4 + T cells and suppressed IL-17 protein expression in T cells (99). A previous T cell study demonstrated that the circulating percentages of neutrophilic MDSCs in graft over that in host disease patients treated with extracorporeal photopheresis increased rapidly (100).…”