PGE2 displays immunosuppressive effects during human active tuberculosis

Pellegrini, Joaquín Miguel; Martin, Candela; Morelli, María Paula; Schander, Julieta Aylén; Tateosian, Nancy Liliana; Amiano, Nicolás Oscar; Rolandelli, Agustín; Palmero, Domingo; Levi, Alberto; Ciallella, Lorena; Colombo, María Isabel; García, Verónica

doi:10.1038/s41598-021-92667-1

Cited by 15 publications

(16 citation statements)

References 64 publications

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“…This may explain our previous discovery of SASP as beneficial suppressor of M.tb infection in mice ( 17 ) which clearly reduced PGE 2 formation in the present study. These results are in line with reports by others showing increased PGE 2 levels in TB disease ( 38 , 39 ) and indicate that high levels of PGE 2 may reduce the bacterial clearance ability of macrophages related to the severe inflammatory processes in these phagocytes. In this respect, our current results show that M1-MDM exposed to MTB-CM produced high levels of TNF-α, IL-1β and IL-6 which was also suppressed by SASP.…”

Section: Discussionsupporting

confidence: 93%

“…All these findings support the notion that excessive PGE 2 is associated with severe inflammation, persisting tissue damage, and poor bacterial clearance ( 42 ). On the other hand, PGE 2 suppressed the excessive inflammatory immune response of the human host against M.tb infection ( 39 ). In fact, PGE 2 has also been suggested to confer protective responses during TB disease.…”

Section: Discussionmentioning

confidence: 99%

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Mycobacterium tuberculosis-Induced Upregulation of the COX-2/mPGES-1 Pathway in Human Macrophages Is Abrogated by Sulfasalazine

et al. 2022

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Macrophages are the primary human host cells of intracellular Mycobacterium tuberculosis (M.tb) infection, where the magnitude of inflammatory reactions is crucial for determining the outcome of infection. Previously, we showed that the anti-inflammatory drug sulfasalazine (SASP) significantly reduced the M.tb bactericidal burden and histopathological inflammation in mice. Here, we asked which genes in human inflammatory macrophages are affected upon infection with M.tb and how would potential changes impact the functional state of macrophages. We used a flow cytometry sorting system which can distinguish the dead and alive states of M.tb harbored in human monocyte-derived macrophages (MDM). We found that the expression of cyclooxygenase-2 and microsomal prostaglandin E2 synthase (mPGES)-1 increased significantly in tagRFP+ MDM which were infected with alive M.tb. After exposure of polarized M1-MDM to M.tb (H37Rv strain)-conditioned medium (MTB-CM) or to the M.tb-derived 19-kD antigen, the production of PGE2 and pro-inflammatory cytokines increased 3- to 4-fold. Upon treatment of M1-MDM with SASP, the MTB-CM-induced expression of COX-2 and the release of COX products and cytokines decreased. Elevation of PGE2 in M1-MDM upon MTB-CM stimulation and modulation by SASP correlated with the activation of the NF-κB pathway. Together, infection of human macrophages by M.tb strongly induces COX-2 and mPGES-1 expression along with massive PGE2 formation which is abrogated by the anti-inflammatory drug SASP.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis-Induced Upregulation of the COX-2/mPGES-1 Pathway in Human Macrophages Is Abrogated by Sulfasalazine

et al. 2022

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“…We demonstrated that PGE2 augmented the percentage of LC3 + neutrophils and monocytes upon Mtb -Ag stimulation. Furthermore, the exogenous addition of this eicosanoid triggered a functional autophagy flux both in monocytes and lymphocytes from TB patients ( Pellegrini et al., 2021 ). Thus, according to our results, PGE2 might be a new target for the development of novel therapeutic tools to fight Mtb .…”

Section: Autophagy In Tb Patientsmentioning

confidence: 99%

“…However, the immune response against Mtb is highly complex. The outcome of TB infection depends, at least in part, on several immune mediators that display critical temporal roles on the host microenvironment ( Sodhi et al., 1997 ; Ottenhoff et al., 1998 ; Chen et al., 2008 ; Pasquinelli et al., 2009 ; Cooper, 2010 ; Jurado et al., 2012 ; Mayer-Barber et al., 2014 ; Pellegrini et al., 2021 ). It has been suggested that host-directed therapies (HDT) could be untapped strategies as complementary therapies against TB, augmenting the host defences and/or limiting tissue damage associated with infection ( Martínez-Colón and Moore, 2018 ; Wan et al., 2018 ; Xiong et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Shedding Light on Autophagy During Human Tuberculosis. A Long Way to Go

Pellegrini

Tateosian

Morelli

et al. 2022

Front. Cell. Infect. Microbiol.

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Immunity against Mycobacterium tuberculosis (Mtb) is highly complex, and the outcome of the infection depends on the role of several immune mediators with particular temporal dynamics on the host microenvironment. Autophagy is a central homeostatic mechanism that plays a role on immunity against intracellular pathogens, including Mtb. Enhanced autophagy in macrophages mediates elimination of intracellular Mtb through lytic and antimicrobial properties only found in autolysosomes. Additionally, it has been demonstrated that standard anti-tuberculosis chemotherapy depends on host autophagy to coordinate successful antimicrobial responses to mycobacteria. Notably, autophagy constitutes an anti-inflammatory mechanism that protects against endomembrane damage triggered by several endogenous components or infectious agents and precludes excessive inflammation. It has also been reported that autophagy can be modulated by cytokines and other immunological signals. Most of the studies on autophagy as a defense mechanism against Mycobacterium have been performed using murine models or human cell lines. However, very limited information exists about the autophagic response in cells from tuberculosis patients. Herein, we review studies that face the autophagy process in tuberculosis patients as a component of the immune response of the human host against an intracellular microorganism such as Mtb. Interestingly, these findings might contribute to recognize new targets for the development of novel therapeutic tools to combat Mtb. Actually, either as a potential successful vaccine or a complementary immunotherapy, efforts are needed to further elucidate the role of autophagy during the immune response of the human host, which will allow to achieve protective and therapeutic benefits in human tuberculosis.

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“…The second immunosuppressive mechanism comprises the action of immune checkpoints and inhibitory receptors, extensively investigated in the context of cancer, albeit more recently during viral and bacterial infections [ 162 , 163 , 164 , 165 ]. Their contribution to brucellosis pathogenesis and persistence remains, so far, an open field.…”

Section: Limiting Host Immunity To Establish Chronic Brucel...mentioning

confidence: 99%

Immunosuppressive Mechanisms in Brucellosis in Light of Chronic Bacterial Diseases

2022

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Brucellosis is considered one of the major zoonoses worldwide, constituting a critical livestock and human health concern with a huge socio-economic burden. Brucella genus, its etiologic agent, is composed of intracellular bacteria that have evolved a prodigious ability to elude and shape host immunity to establish chronic infection. Brucella’s intracellular lifestyle and pathogen-associated molecular patterns, such as its specific lipopolysaccharide (LPS), are key factors for hiding and hampering recognition by the immune system. Here, we will review the current knowledge of evading and immunosuppressive mechanisms elicited by Brucella species to persist stealthily in their hosts, such as those triggered by their LPS and cyclic β-1,2-d-glucan or involved in neutrophil and monocyte avoidance, antigen presentation impairment, the modulation of T cell responses and immunometabolism. Attractive strategies exploited by other successful chronic pathogenic bacteria, including Mycobacteria, Salmonella, and Chlamydia, will be also discussed, with a special emphasis on the mechanisms operating in brucellosis, such as granuloma formation, pyroptosis, and manipulation of type I and III IFNs, B cells, innate lymphoid cells, and host lipids. A better understanding of these stratagems is essential to fighting bacterial chronic infections and designing innovative treatments and vaccines.

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PGE2 displays immunosuppressive effects during human active tuberculosis

Cited by 15 publications

References 64 publications

Mycobacterium tuberculosis-Induced Upregulation of the COX-2/mPGES-1 Pathway in Human Macrophages Is Abrogated by Sulfasalazine

Mycobacterium tuberculosis-Induced Upregulation of the COX-2/mPGES-1 Pathway in Human Macrophages Is Abrogated by Sulfasalazine

Shedding Light on Autophagy During Human Tuberculosis. A Long Way to Go

Immunosuppressive Mechanisms in Brucellosis in Light of Chronic Bacterial Diseases

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