Elevated CO₂selectively inhibits interleukin‐6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage

Abstract

Elevated blood and tissue CO(2), or hypercapnia, is common in severe lung disease. Patients with hypercapnia often develop lung infections and have an increased risk of death following pneumonia. To explore whether hypercapnia interferes with host defense, we studied the effects of elevated P(CO2) on macrophage innate immune responses. In differentiated human THP-1 macrophages and human and mouse alveolar macrophages stimulated with lipopolysaccharide (LPS) and other Toll-like receptor ligands, hypercapnia inhibited expression of tumor necrosis factor and interleukin (IL)-6, nuclear factor (NF)-kappaB-dependent cytokines critical for antimicrobial host defense. Inhibition of IL-6 expression by hypercapnia was concentration dependent, rapid, reversible, and independent of extracellular and intracellular acidosis. In contrast, hypercapnia did not down-regulate IL-10 or interferon-beta, which do not require NF-kappaB. Notably, hypercapnia did not affect LPS-induced degradation of IkappaB alpha, nuclear translocation of RelA/p65, or activation of mitogen-activated protein kinases, but it did block IL-6 promoter-driven luciferase activity in mouse RAW 264.7 macrophages. Elevated P(CO2) also decreased phagocytosis of opsonized polystyrene beads and heat-killed bacteria in THP-1 and human alveolar macrophages. By interfering with essential innate immune functions in the macrophage, hypercapnia may cause a previously unrecognized defect in resistance to pulmonary infection in patients with advanced lung disease.

NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells

“…It is clear that there are profound immune and inflammatory signaling consequences for NF-kB target gene expression against a background of elevated CO 2 (10%). Our observations are consistent with those made by both Takeshita et al (12) and Wang et al (22). In mammalian models, the beneficial immunomodulatory effects of CO 2 have been demonstrated in acute respiratory distress syndrome, hypercapnic acidosis, and sepsis (7,8,26).…”

“…Furthermore, it appears that the NF-kB pathway may be modified at more than one point by CO 2 , as evidenced by the preservation of cytoplasmic IkBa in response to ligand stimulation at elevated CO 2 (5-10%). This finding is consistent with observations made in hypercapnic acidosis by Takeshita et al (12), but different from a recent article from Wang et al using hypercapnia (22). It is clear that there are profound immune and inflammatory signaling consequences for NF-kB target gene expression against a background of elevated CO 2 (10%).…”

“…The full array data are included as Supplemental Table I and include evidence for a global effect of CO 2 on the NF-kB transcriptional response. Other genes of interest that were differentially regulated in the array include TLR family members and other inflammatory mediators such as IL-6, which has recently been described to be affected by elevated CO 2 in macrophages (22). Interestingly, the expression of the genes associated with a proinflammatory response (CCL2, ICAM1, and TNF-a) were blunted at 10% CO 2 , whereas expression of IL-10, which is known to have anti-inflammatory properties (23), was enhanced at 10% CO 2 in the presence of LT (Fig.…”

Elevated CO2suppresses specific Drosophila innate immune responses and resistance to bacterial infection

“…Our results show that hypercapnia inhibits expression of Rel targets downstream of, or in parallel to, proteolytic cleavage of the IB␣-like domain of Rel. This result parallels the findings of Wang et al (48) who show in mammalian macrophages that hypercapnia suppress NF-B-regulated genes without affecting proteolysis of IB␣. We propose two models for how a CO 2 response pathway might suppress transcription of Drosophila Rel targets such as Dpt.…”

Pleural Hypercarbia After Lung Surgery Is Associated With Persistent Alveolopleural Fistulae

“…24 Hypercarbia upregulates microRNA-183, which suppresses the mitochondrial enzyme isocitrate dehydrogenase 2 and inhibits oxygen consumption and adenosine triphosphate production. Hypercarbia can also prevent macrophage phagocytosis of pathogens and cellular debris, 13,25,26 which might further impair alveolar epithelial healing.…”