Harmful Effects of Granulocytic Myeloid-Derived Suppressor Cells on Tuberculosis Caused by Hypervirulent Mycobacteria

Abstract

Background The role of myeloid-derived suppressor cells (MDSCs) in severe tuberculosis patients who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. Methods This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. Results CD11b +GR1 int population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b +GR1 int (Ly6G intLy6C int) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T cell suppression occurred concomitantly with CD11b +GR1 int cell accumulation in the lungs. Furthermore, lung and bone-marrow GR1 + cells suppressed both T cell proliferation and IFN-γ production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. Conclusions Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies.

P2x7 Receptor Signaling Blockade Reduces Lung Inflammation and Necrosis During Severe Experimental Tuberculosis

“…The population of GR-1 + myeloid cells was particularly affected by P2X7 pharmacological blockade. Characterized as granulocytic myeloid-derived suppressor cells, GR-1 + cells accumulate massively in the lungs during the final stage of hypervirulent mycobacterial infection, promoting bacterial growth and the development of necrotizing pneumonia ( Barbosa Bomfim et al., 2021 ). This immature myeloid cell population is generated by emergency hematopoiesis in response to excessive or chronic infections ( Boettcher and Manz, 2017 ).…”

“…The pharmacological inhibition of adenosine receptors increased the frequency of IFN-γ-producing CD4 + T cells ( Amaral et al., 2019b ), which are the major source of IFN-γ in the lungs of MP287/03-infected mice at day 28 p.i. ( Barbosa Bomfim et al., 2021 ). The protection of infected lung tissue resulting from P2X7 inhibition may prevent ATP release and, consequently, the accumulation of adenosine in the extracellular environment, leading to an increase in IFN-γ production by CD4 + T cells.…”

“…In addition, the accumulation of myeloid-derived suppressor cells in the lungs has been shown to be dependent on P2X7 activation ( Bomfim et al., 2017 ). This population of immature myeloid cells migrates from the bone marrow to the lungs when the disease gets worse and becomes a permissive niche for the replication of the bacillus, allowing the spread of the infection in the lungs ( Knaul et al., 2014 ; Tsiganov et al., 2014 ; Lovewell et al., 2020 ; Barbosa Bomfim et al., 2021 ).…”

Neutrophils in Tuberculosis: Cell Biology, Cellular Networking and Multitasking in Host Defense

“…Indeed, PD-1-mediated inhibition is critical for Mtb control in macaques, and PD-1 blockade promotes TB reactivation [ 176 ], yet a role for neutrophils as negative regulators awaits validation. Subsets of neutrophils termed granulocytic myeloid-derived suppressor cells inhibit the proliferation of T-cells as well as the release of cytokines in Mtb -infected mice [ 177 , 178 ]. Circulating and lung-residing suppressive neutrophils, including LDGs, have also been identified in TB patients [ 179 , 180 , 181 ].…”

“…Are all neutrophils equal in supporting permissiveness to bacteria, or triggering tissue damage? Novel data indicate that long-lived Ly-6G dim neutrophils are more permissive for Mtb replication [ 190 ] and suppressive neutrophils, including low-density neutrophils and granulocytic myeloid-derived suppressor cells, are associated with exuberant inflammation [ 177 , 178 , 181 ]. Neutrophils imprint on tissue homeostasis [ 214 ].…”