Hypercapnia Inhibits Autophagy and Bacterial Killing in Human Macrophages by Increasing Expression of Bcl-2 and Bcl-xL

Casalino‐Matsuda, S. Marina; Nair, Aisha; Beitel, Greg J.; Gates, Khalilah L.; Sporn, Peter H. S.

doi:10.4049/jimmunol.1500150

Cited by 52 publications

(50 citation statements)

References 77 publications

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“…Consistent with this hypothesis, we and others have shown that hypercapnia inhibits expression of IL-6, TNF and other cytokines important for host defense (15-17). Cummins and colleagues have shown that elevated CO 2 inhibits activation of the canonical NF-κB pathway (18, 19) that drives expression of many host defense genes, while promoting activation of the non-canonical NF-κB component RelB (18, 19), whose function is largely anti-inflammatory and immunosuppressive.…”

Section: Introductionsupporting

confidence: 85%

“…However, in our in vitro studies, suppression of cytokine gene expression, phagocytosis and autophagy by elevated CO 2 levels was independent of acidosis (15-17). Further, hypercapnia increased the mortality of bacterial pneumonia in mice with acute and chronic hypercapnia to the same degree, despite more severe acidosis in animals with acute hypercapnia compared to chronic hypercapnia (due to renal compensation in the latter group) (16).…”

Section: Introductionmentioning

confidence: 54%

“…Cummins and colleagues have shown that elevated CO 2 inhibits activation of the canonical NF-κB pathway (18, 19) that drives expression of many host defense genes, while promoting activation of the non-canonical NF-κB component RelB (18, 19), whose function is largely anti-inflammatory and immunosuppressive. We also showed that hypercapnia suppresses phagocytosis, generation of reactive oxygen species and autophagy (15-17), all key phagocyte antimicrobial functions. Furthermore, we showed that hypercapnia reduces bacterial clearance and increases mortality in a mouse model of Pseudomonas pneumonia (16).…”

Section: Introductionmentioning

confidence: 75%

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Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen

Helenius

Haake

Kwon

et al. 2016

The Journal of Immunology

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Hypercapnia, elevated partial pressure of carbon dioxide (PCO2) in blood and tissue, develops in many patients with chronic severe obstructive pulmonary disease and other advanced lung disorders. Patients with advanced disease frequently develop bacterial lung infections, and hypercapnia is a risk factor for mortality in such individuals. We previously demonstrated that hypercapnia suppresses induction of NF-κB-regulated innate immune response genes required for host defense in human, mouse and Drosophila cells, and increases mortality from bacterial infections in both mice and Drosophila. However, the molecular mediator(s) of hypercapnic immune suppression are undefined. Here, we report a genome-wide RNAi screen in Drosophila S2* cells stimulated with bacterial peptidoglycan (PGN). The screen identified 16 genes with human orthologs whose knockdown reduced hypercapnic suppression of the gene encoding the antimicrobial peptide (AMPs) Diptericin (Dipt), but did not increase Dipt mRNA levels in air. In vivo tests of one of the strongest screen hits, Zfh2 (mammalian orthologs ZFHX3/ATBF1 and ZFHX4), demonstrate that reducing zfh2 function using a mutation or RNAi improves survival of flies exposed to elevated CO2 and infected with S. aureus. Tissue-specific knockdown of zfh2 in the fat body, the major immune and metabolic organ of the fly, mitigates hypercapnia-induced reductions in Dipt and other AMPs and improves resistance of CO2-exposed flies to infection. Zfh2 mutations also partially rescue hypercapnia-induced delays in egg hatching, suggesting that Zfh2's role in mediating responses to hypercapnia extends beyond the immune system. Together, these results identify Zfh2 as the first in vivo mediator of hypercapnic immune suppression.

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Section: Introductionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 75%

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Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen

Helenius

Haake

Kwon

et al. 2016

The Journal of Immunology

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“…lysosomal degradation of HIF-␣ protein, elevated CO 2 has recently been demonstrated to inhibit macroautophagy in macrophages (44).…”

Section: Discussionmentioning

confidence: 99%

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Selfridge¹,

Cavadas

Scholz³

et al. 2016

Journal of Biological Chemistry

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Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-␣ protein stability and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O 2 -dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-␣ protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO 2 . Bafilomycin A1, a specific inhibitor of vacuolar-type H ؉ -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-␣ protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-␣ subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.Current atmospheric CO 2 levels are relatively low when compared with those recorded throughout the natural history of the planet (1). Not surprisingly, therefore, a range of organisms as diverse as bacteria, fungi, plants, and mammals mount physiologic responses to hypercapnia (2). It is now clear that CO 2 , like other physiologic gases such as oxygen and nitric oxide, can be sensed by cells and can elicit adaptive transcriptional responses (2-4).Because O 2 consumption is coupled to CO 2 production, an intimate inverse relationship exists between the levels of these gases in cells and tissues. Furthermore, O 2 and CO 2 levels may become perturbed during certain pathophysiologic states (3, 5). Hypoxia and hypercapnia can co-occur in respiratory disorders such as obstructive sleep apnea syndrome, pneumonia, and chronic obstructive pulmonary disease (6, 7). In acute lung injury hypoxia may arise, whereas permissive hypercapnia is often tolerated as a protective ventilatory strategy in patients presenting with this disorder (8, 9). Hypercapnia and hypoxia also influence inflammatory processes (10 -12). During inflammation, oxygen consumption is significantly elevated, leading to tissue hypoxia. It is likely that this also has consequences for tissue CO 2 levels (3, 11). HIF 8 (which comprises the HIF-1, HIF-2, and HIF-3 isoforms) is the master transcriptional regulator of the cellular response to hypoxia (13). Canonical HIF degradation relies on the activity of O 2 -dependent prolyl hydroxylases 1-3 (14). In normoxia, prolyl hydroxylases enzymatically modify HIF-␣ subunits on proli...

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“…11 In addition, we have shown that hypercapnia inhibits phagocytosis, autophagy, and bacterial killing in mouse and human macrophages. 9,12 Interestingly, elevated CO 2 has immunosuppressive effects in Drosophila , as well as in mammalian systems. We found that hypercapnia inhibits expression of antimicrobial peptides (AMPs) in Drosophila S2* cells and that it decreases bacterial clearance and increases the mortality of bacterial infections in Drosophila in vivo.…”

Section: Introductionmentioning

confidence: 99%

Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression

et al. 2016

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Patients with severe lung disease may develop hypercapnia, elevation of the levels of CO2 in the lungs and blood, which is associated with increased risk of death, often from infection. To identify compounds that ameliorate the adverse effects of hypercapnia, we performed a focused screen of 8832 compounds using a CO2-responsive luciferase reporter in Drosophila S2* cells. We found that evoxine, a plant alkaloid, counteracts the CO2-induced transcriptional suppression of antimicrobial peptides in S2* cells. Strikingly, evoxine also inhibits hypercapnic suppression of interleukin-6 and the chemokine CCL2 expression in human THP-1 macrophages. Evoxine's effects are selective, since it does not prevent hypercapnic inhibition of phagocytosis by THP-1 cells or CO2-induced activation of AMPK in rat ATII pulmonary epithelial cells. The results suggest that hypercapnia suppresses innate immune gene expression by definable pathways that are evolutionarily conserved and demonstrate for the first time that specific CO2 effects can be targeted pharmacologically.

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Hypercapnia Inhibits Autophagy and Bacterial Killing in Human Macrophages by Increasing Expression of Bcl-2 and Bcl-xL

Cited by 52 publications

References 77 publications

Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen

Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen

Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia

Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression

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