Corticosteroids protect infected cells against mycobacterial killing in vitro

Tükenmez, Hasan; Edström, Isabel; Kalsum, Sadaf; Braian, Clara; Ummanni, Ramesh; Fick, Stina Berglund; Sundin, Charlotta; Lerm, Maria; Elofsson, Mikael; Larsson, Christer

doi:10.1016/j.bbrc.2019.02.044

Cited by 9 publications

(7 citation statements)

References 18 publications

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“…Similar results have been found in human monocyte-derived Mϕs infected with Mtb and treated with different corticosteroids, including DEX. All the corticosteroids tested reduced intracellular bacterial growth [ 56 ]. This demonstrated that DEX could decrease intracellular Mtb growth not only in mice Mϕs but also in human Mϕs, which is promising in the treatment of TB.…”

Section: Discussionmentioning

confidence: 99%

Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis

et al. 2023

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Tuberculosis (TB) is the deadliest disease caused by a bacterial agent. Glucocorticoids (GCs) have a typical anti-inflammatory effect, but recently it has been shown that they can present proinflammatory activity, mainly by increasing molecules from innate immunity. In the current study, we evaluated the effect of low doses of dexamethasone on Mycobacterium tuberculosis in vivo and in vitro. We used an established mice model of progressing tuberculosis (TB) in the in vivo studies. Intratracheal or intranasal dexamethasone therapy administered with conventional antibiotics in the late stage of the disease decreased the lung bacilli load and lung pneumonia, and increased the survival of the animals. Finally, the treatment decreased the inflammatory response in the SNC and, therefore, sickness behavior and neurological abnormalities in the infected animals. In the in vitro experiments, we used a cell line of murine alveolar macrophages infected with Mtb. Low-dose dexamethasone treatment increased the clearance capacity of Mtb by MHS macrophages, MIP-1α, and TLR2 expression, decreased proinflammatory and anti-inflammatory cytokines, and induced apoptosis, a molecular process that contributes to the control of the mycobacteria. In conclusion, the administration of low doses of dexamethasone represents a promising adjuvant treatment for pulmonary TB.

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Section: Discussionmentioning

confidence: 99%

Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis

et al. 2023

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“…This analysis and our findings, shown in Figure 7, suggest that deoxycorticosterone acetate keeps M. tuberculosis-infected MDMs in a metabolically active state. Excess amounts of neurocorticosteroids, such as deoxycorticosterone acetate, can cause hypertension (69), although suboptimal doses can JCI Insight 2022;7 (22):e152357 https://doi.org/10.1172/jci.insight.152357 prevent cytolysis of mycobacteria-infected lung fibroblast cells and reduce bacterial growth in MDMs (70). These effects are mediated through glucocorticoid receptors (70).…”

Section: Discussionmentioning

confidence: 99%

“…Excess amounts of neurocorticosteroids, such as deoxycorticosterone acetate, can cause hypertension (69), although suboptimal doses can JCI Insight 2022;7 (22):e152357 https://doi.org/10.1172/jci.insight.152357 prevent cytolysis of mycobacteria-infected lung fibroblast cells and reduce bacterial growth in MDMs (70). These effects are mediated through glucocorticoid receptors (70). The nonconverters in the current cohort were healthy, suggesting that suboptimal doses of deoxycorticosterone acetate in plasma help fight against M. tuberculosis infection.…”

Section: Discussionmentioning

confidence: 99%

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Tripathi¹,

Devalraju²,

Neela³

et al. 2022

JCI Insight

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We characterized the phenotype and function of various immune cells in a large group of LTBI -HHCs (nonconverters) of patients with TB (a total of 452 individuals). We performed these measures at baseline (0 months) and follow-up (24 months) while monitoring the participants for conversion to LTBI. By following a large cohort of HHCs of patients with TB and performing transcriptional and metabolomic studies, we determined whether resistance to M. tuberculosis infection is preceded by specific changes in the transcriptional profile. We also determined whether metabolites regulate macrophage metabolism and function to restrict M. tuberculosis growth. ResultsPrevalence of nonconverters in the HHCs of patients with TB. At baseline, among 990 HHCs, 538 (54.3%) were positive and 452 (45.6%) were negative for LTBI by the IFN-γ release assay (IGRA) as described in the Methods (Supplemental Table 1; supplemental material available online with this article; https://doi.org/10.1172/ jci.insight.152357DS1). We followed these 452 LTBI -HHCs for 2 years at 4-month intervals (study plan is shown in Figure 1A). Exposure to index patients was determined following the criteria mentioned in previous studies (10-14) and in the Methods section. Among the 452 LTBI -HHCs, 96 (21.2%) became IGRA + (converters) over 2 years of follow-up. Despite similar exposure levels, 293 (64.8%) HHCs remained IGRA -(nonconverters) until the end of the study (Table 1 and Supplemental Data 1). As shown in Supplemental Data 1, all (n = 96) converters consistently produced IFN-γ in response to M. tuberculosis antigens. The demographic details of converters and nonconverters are shown in Table 1 and Supplemental Table 1.Immune cell phenotypes of converters and nonconverters. The innate immune response is critical to clear M. tuberculosis infection and may play an important role in preventing LTBI conversion (15-18). We determined various immune cell populations at baseline and during the follow-up visits (24 months) in freshly isolated peripheral blood mononuclear cells (PBMCs) of age-and sex-matched nonconverters (n = 293) and converters (n = 96). At baseline, in fresh PBMCs of nonconverters, the percentages of CD14 + and CD3 -CD56 + CD27 + CCR7 + memory-like NK cells were significantly higher than those of converters (Figure 1B and Supplemental Figure 1). No significant differences in CD4 + , CD16 + , CD14 + CD16 + , CD16 + CD56 + , or CD4 + CD25 + FoxP3 + cells were found in the PBMCs of nonconverters and converters (Figure 1B). As shown in Figure 1B, the percentage of memory-like NK cells significantly decreased in converters at follow-up. However, in nonconverters, the percentages of the cells remained the same throughout the study (Figure 1B).Cytokine and chemokine production by the PBMCs of converters and nonconverters in response to M. tuberculosis antigens. Various cytokines and chemokines produced following M. tuberculosis exposure are crucial to the outcome of infection (19,20). We determined cytokine and chemokine production by PBMCs of convert...

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“…This seemingly paradoxical finding is supported by the literature. Tukenmez et al (Tükenmez et al , 2019) found that many different GC formulations individually decreased M. tuberculosis burden in human MDMs. Bongiovanni and co-workers (Bongiovanni et al , 2015) similarly reported that cortisol not only decreased phagocytosis of M. tuberculosis (by ~10%) but that there was a further reduction in the intracellular burden of M. tuberculosis by day 4 of culture in THP-1 macrophages.…”

Section: Discussionmentioning

confidence: 99%

Alpha-1-antitrypsin binds to the glucocorticoid receptor with biological significance in macrophages

Bai

Tomasicchio

et al. 2022

Preprint

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Alpha-1-antitrypsin (AAT), a serine protease inhibitor produced mainly by the liver, is the third most abundant protein in plasma. While a canonical receptor for AAT has not been identified, AAT can be internalized into the cytoplasm and is known to affect gene regulation. Since AAT has significant anti-inflammatory properties affecting many cell types including macrophages, we examined whether AAT binds the cytoplasmic glucocorticoid receptor (GR) in macrophages. We report the novel finding that AAT binds to GR in macrophages using several approaches, including co-immunoprecipitation, mass spectrometry, microscale thermophoresis, and molecular modeling. The mass spectrometry data are available via ProteomeXchange with identifier PXD030989. We further demonstrate that AAT induction of angiopoietin-like 4 protein and AAT inhibition of lipopolysaccharide-induced nuclear factor-kappa B activation and interleukin-8 production are mediated, in part, through AAT-GR interaction. Furthermore, this interaction contributes to a host-protective role against mycobacteria in macrophages. The interaction of AAT and GR described in this study identifies a mechanism for the anti-inflammatory and host-defense properties of AAT

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Corticosteroids protect infected cells against mycobacterial killing in vitro

Cited by 9 publications

References 18 publications

Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis

Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis

Metabolites enhance innate resistance to human Mycobacterium tuberculosis infection

Alpha-1-antitrypsin binds to the glucocorticoid receptor with biological significance in macrophages

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