An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses

Abstract

Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.

Excess fermentation and lactic acidosis as detrimental functions of the gut microbes in treatment-naive TB patients

“…In clinical tuberculosis, the balance between the antibacterial activity of macrophages and tissue destruction by extracellular enzymes, primarily matrix metalloproteinases (MMPs), produced during inflammation is critical to disease outcome and transmission ( Ong et al., 2014 ). Recent studies show that this balance is affected by the extracellular concentration of lactate ( Whittington et al., 2023 ), produced by infected macrophages using glycolysis ( Langston et al., 2017 ). Mechanistically, lactate, on the one hand, improves clearance of MTB in the already infected macrophage by promoting autophagy.…”

“…On the other hand, it markedly suppresses both TNF-α and IFN-γ but leaves IL6 and IL10 unaffected, thereby interfering with further enhancement of anti-MTB activity ( Maoldomhnaigh et al., 2021 ). Moreover, lactate specifically upregulates matrix metalloproteinases that cause lung destruction in the tuberculosis ( Whittington et al., 2023 ), the process known to result in higher morbidity and mortality in the TB treatment ( Ong et al., 2014 ). Thus, recent mechanistic insights underscore the multifaceted effect of lactate on Th1 response with an overall negative impact on the ability to cope with MTB, which is more in line with clinical data.…”

Excess fermentation and lactic acidosis as detrimental functions of the gut microbes in treatment-naive TB patients

“…In clinical tuberculosis, the balance between the antibacterial activity of macrophages and tissue destruction by extracellular enzymes, primarily matrix metalloproteinases (MMPs), produced during inflammation is critical to disease outcome and transmission (Ong et al, 2014). Recent studies show that this balance is affected by the extracellular concentration of lactate (Whittington et al, 2023), which is produced by infected macrophages using glycolysis (Langston et al, 2017). Mechanistically, lactate, on the one hand, improves clearance of MTB in the already infected macrophage by promoting autophagy.…”

“…On the other hand, it markedly suppresses both TNF-α and IFN-γ but leaves IL6 and IL10 unaffected, thereby interfering with further enhancement of anti-MTB activity (Ó Maoldomhnaigh et al, 2021). Moreover, lactate specifically upregulates matrix metalloproteinases that cause lung destruction in tuberculosis (Whittington et al, 2023), the process known to result in higher morbidity and mortality in TB treatment (Ong et al, 2014). Thus, recent mechanistic insights underscore the multifaceted effect of lactate on Th1 response with an overall negative impact on the ability to cope with MTB, which is more in line with clinical data.…”