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

Abstract

The risk of developing severe forms of tuberculosis has increased by the acquired immunodeficiency syndrome (AIDS) epidemic, lack of effective drugs to eliminate latent infection and the emergence of drug-resistant mycobacterial strains. Excessive inflammatory response and tissue damage associated with severe tuberculosis contribute to poor outcome of the disease. Our previous studies using mice deficient in the ATP-gated ionotropic P2X7 receptor suggested this molecule as a promising target for host-directed therapy in severe pulmonary tuberculosis. In this study, we assessed the effects of P2X7 pharmacological blockade on disease severity. First, we observed an increase in P2RX7 gene expression in the peripheral blood of tuberculosis patients compared to healthy donors. Lung leukocytes of mice infected with hypervirulent mycobacteria also showed increased expression of the P2X7 receptor. P2X7 blockade in mice with advanced tuberculosis recapitulated in many aspects the disease in P2X7-deficient mice. P2X7-directed therapy reduced body weight loss and the development of inflammatory and necrotic lung lesions, as well as delayed mycobacterial growth. Lower TNF-α production by lung cells and a substantial reduction in the lung GR-1+ myeloid cell population were observed after P2X7 inhibition. The effector CD4+ T cell population also decreased, but IFN-γ production by lung cells increased. The presence of a large population with characteristics of myeloid dendritic cells, as well as the increase in IL-6 production by lung cells, also indicate a qualitative improvement in the pulmonary immune response due to P2X7 inhibition. These findings support the use of drugs that target the P2X7 receptor as a therapeutic strategy to improve the outcome of pulmonary tuberculosis.

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections

“…P2RX7 is a low affinity eATP receptor (Di Virgilio et al, 2017), therefore its action has been associated with eATP accumulation induced by tissue cell death during infections (Amaral et al, 2014;Borges da Silva et al, 2020;Di Virgilio et al, 2017). Multiple immune cells and lung epithelial cells express P2RX7, and our group has previously shown that pharmacological P2RX7 inhibition led to decreased CD4 + T cell numbers in the lung parenchyma in response to MP287 (Santiago-Carvalho et al, 2021). Our results expand these findings by identifying that the infection-induced accumulation of lung parenchymal CD4 + T cells depends on P2RX7 signaling directly on T cells.…”

“…Whether P2RX7 serves as a microenvironmental sensor for lung CD4 + T cell accumulation, and whether P2RX7-expressing CD4 + T cells are the main promoter of lung damage rather than other cell types is not understood. Of note, we have found that, in correlation with protection from disease, transient P2RX7 blockade led to reduced numbers of CD69 + lung-parenchymal CD4 + T cells (Santiago-Carvalho et al, 2021). Moreover, P2RX7 is known to play an important role in the establishment of tissueresident memory (T RM ) CD8 + T cells in response to systemic viruses (Borges da Silva et al, 2018;Borges da Silva et al, 2020).…”

P2X7 receptor as the regulator of T-cell function in intestinal barrier disruption

“…The selectively P2X7 antagonist was proven to significantly inhibit the innate immune cells and upregulate the immunosuppressive-associated T cells, indicating that this antagonist may be a kind of potential treatment[ 175 ]. The effect of P2X7-blockade drug has also been demonstrated in the mouse models with advanced tuberculosis[ 176 ]. In addition to the above intracellular signaling pathways (MAPK pathway), previous studies verified that P2X7R also regulated MyD88/NF-κB and PI3K/Akt/mTOR signaling pathways in innate and adaptive immune responses, which suggested that the key proteins in these pathways can be considered as novel therapeutic targets[ 177 ].…”

The Role of Purinergic P2X7 Receptor in Inflammation and Cancer: Novel Molecular Insights and Clinical Applications

“…The inhibition of P2X7R signalling can also lead to antimycobacterial activities. For instance, P2X7R inhibition with Brilliant blue G (BBG) can prevent the development of a severe form of Micobacterium tuberculosis -driven tuberculosis in mice with experimental advanced pulmonary tuberculosis [ 110 ], while the adoptive transfer of P2X7R KO hematopoietic cells in mice can lead to a reduced pneumonia as well as a lower lung Micobacterium bovis burden in comparison with WT mice [ 95 ]. Furthermore, P2X7R has been reported to be implicated during the Gram-positive bacterial infection responsible for sepsis .…”