Heme oxygenase 1 controls early innate immune response of macrophages to Salmonella Typhimurium infection: Heme oxygenase 1 expression affects Salmonella infection
Open accessAbstract
Macrophages are central for the immune control of intracellular microbes. Heme oxygenase 1 (HO-1, hmox) is the first and rate limiting enzyme in the breakdown of heme originating from degraded senescent erythrocytes and heme-proteins, yielding equal amounts of iron, carbon monoxide and biliverdin. HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin. In view of the essential role of iron for the growth and proliferation of intracellular bacteria along with known effects of the metal on innate immune function, we examined whether HO-1 plays a role in the control of infection with the intracellular bacterium Salmonella Typhimurium. We studied the course of infection in stably-transfected murine macrophages (RAW264.7) bearing a tetracycline-inducible plasmid producing hmox shRNA and in primary HO-1 knockout macrophages. While uptake of bacteria into macrophages was not affected, a significantly reduced survival of intracellular Salmonella was observed upon hmox knockdown or pharmacological hmox inhibition, which was independent of Nramp1 functionality. This could be traced to limitation of iron availability for intramacrophage bacteria along with enhanced stimulation of innate immune effector pathways, including the formation of reactive oxygen and nitrogen species and increased TNF-α expression. Mechanistically, these latter effects result from intracellular iron limitation with subsequent activation of NF-κB and further inos, tnfa and p47phox transcription along with reduced formation of the anti-inflammatory and radical scavenging molecules, CO and biliverdin as a consequence of HO-1 silencing. Taken together our data provide novel evidence that the infection-driven induction of HO-1 exerts detrimental effects in the early control of Salmonella infection, whereas hmox inhibition can favourably modulate anti-bacterial immune effector pathways of macrophages and promote bacterial elimination.
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- Findingown data
Transferrin-bound iron and non-transferrin-bound iron uptake was significantly increased in uninfected and infected hmox.sh cells compared with ctrl.sh cells.
“These changes were paralleled by a significant increase in transferrin- bound iron (TBI) and non-transferrin bound iron (NTBI) uptake by uninfected and infected hmox.sh cells as compared to ctrl.sh. (Fig. 2D and E).”
Quote in the paperSubstantial claim - Findingown data
Increased expression of tnfa, il6, and lcn2 was also seen in hmox knockdown cells upon treatment with heat-inactivated Salmonella or lipopolysaccharide.
“Of note, in comparison to control macrophages an increased expression of tnfa, il6 and lcn2 was also seen in hmox knockdown cells upon treatment with either heat-inactivated Salmonella (Fig. 4) or lipopolysaccharide (data not shown), pointing to a general and early immune de-activating effect of hmox in inflammatory macrophages.”
Quote in the paperSubstantial claim - Findingown data
RNS production, measured as nitrite concentration in culture supernatants, was increased in hmox.sh macrophages.
“Notably, the production of RNS, measured via the concentration of the stable NO end-product nitrite in culture supernatants, was also increased in hmox.sh macrophages (Fig. 5E).”
Quote in the paperSubstantial claim - Findingown data
hmox.sh macrophages exhibited higher phosphorylation of the NF-κB p65 subunit compared with ctrl.sh macrophages.
“Western blot experiment data demonstrated that hmox.sh macrophages exhibit higher phosphorylation of the NF-κB p65 subunit in comparison to crtl.sh macrophages (Fig. 7B).”
Quote in the paperSubstantial claim - Findingown data
Infection of RAW264.7 macrophages with hmox shRNA caused a significant time-dependent decrease in intracellular Salmonella numbers compared with control shRNA macrophages.
“Infection of these cells with S. Typhimurium resulted in significant and time-dependent decrease of bacterial numbers within macrophages as compared to macrophages stable transfected with control shRNA expressing luciferase (Fig. 1D).”
Quote in the paperSubstantial claim
- Findingown data
The Salmonella triple mutant strain acquired significantly less iron than wild-type Salmonella.
“The Salmonella triple mutant strain acquired significantly less iron than wt Salmonella (Fig. 2I).”
Quote in the paperNot a substantial claim - Findingown data
Enhanced iron export corresponded to increased Fpn1 protein levels in macrophages infected with Salmonella.
“Importantly, the enhanced iron export corresponded to increased Fpn1 protein levels in macrophages infected with Salmonella, as determined by Western Blot analysis (Fig. 2 G).”
Quote in the paperSubstantial claim - Findingown data
hmox.sh phagocytes had significantly lower total intracellular iron contents following infection compared with infected control cells, including when infected with an iron-acquisition-deficient Salmonella mutant.
“We found that hmox.sh phagocytes exhibited significantly lower iron contents following infection compared to infected control cells, which was also true when the infection was performed with a Salmonella mutant strain deficient in iron acquisition (Fig. 2H).”
Quote in the paperSubstantial claim - Findingown data
Blockade of HO-1 activity by ZnPP resulted in comparable reductions of bacterial numbers in RAW264.7 cells with functional and non-functional Nramp1.
“However, blockade of HO-1 activity by ZnPP resulted in comparable reductions of bacterial numbers in both cell types suggesting that the growth promoting effect of HO-1 towards intramacrophage Salmonella is independent of Nramp1 functionality (Figure S2 B).”
Quote in the paperSubstantial claim - Findingown data
NAC treatment significantly augmented the bacterial load of hmox.sh and control.sh macrophages to a comparable level.
“NAC treatment significantly augmented the bacterial load of hmox.sh and control.sh macrophages to a comparable level (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
Upon Salmonella infection, hmox knockdown macrophages expressed significantly higher levels of lcn2.
“Importantly, upon infection with Salmonella, hmox knockdown macrophages expressed significantly higher levels of the anti-microbial siderophore scavenging peptide lipocalin 2 (lcn2).”
Quote in the paperSubstantial claim - Findingown data
Doxycycline induction of hmox shRNA reduced hmox mRNA expression by 80 to 90% in RAW264.7 cells.
“Doxycycline induction caused an overall reduction of hmox mRNA expression of 80 to 90%.”
Quote in the paperSubstantial claim - Findingown data
hmox1 knockdown was not compensated by an increase in hmox2 expression.
“Notably, hmox1 knockdown in the cells was not compensated by an increase of hmox2 expression (Supplemental Figure S3 B).”
Quote in the paperNot a substantial claim - Findingown data
In uninfected hmox.sh and ctrl.sh macrophages, tfr1 and dmt1 expression did not differ.
“The iron acquisition genes, transferrin receptor 1 (TfR1, tfr1) and divalent metal transporter 1 (Dmt1, dmt1), showed no difference in expression between uninfected hmox.sh and ctrl.sh macrophages.”
Quote in the paperNot a substantial claim - Findingown data
Uptake of Salmonella into macrophages was not affected by hmox knockdown or HO-1 knockout.
“While uptake of bacteria into macrophages was not affected, a significantly reduced survival of intracellular Salmonella was observed upon hmox knockdown or pharmacological hmox inhibition, which was independent of Nramp1 functionality.”
- Also stated in: § Intramacrophage bacterial replication is augmented by heme oxygenase 1 · plain
“This observation could not be attributed to differences in Salmonella uptake or containment because intramacrophage bacterial numbers were the same in hmox knockdown and control macrophages as well as in primary wild type and HO-1 knockout bone marrow derived macrophages at 1 h after infection (Fig. 1B, C and G).”
Quote in the paperSubstantial claim - Also stated in: § Intramacrophage bacterial replication is augmented by heme oxygenase 1 · plain
- Findingown data
p65 DNA binding activity was significantly increased in hmox knockdown cells infected with Salmonella Typhimurium compared with infected ctrl.sh cells.
“Quantification of the specific DNA binding activity to the NF-κB subunit p65 revealed significantly increased p65 binding activity in the hmox knockdown cells infected with Salmonella Typhimurium compared to infected ctrl.sh cells (Fig. 7A).”
Quote in the paperSubstantial claim - Findingown data
Pre-treatment with the HO-1 inhibitor ZnPP significantly reduced Salmonella CFU recovered from RAW264.7 macrophages after 24 h compared with solvent-treated controls.
“The number of Salmonella colony forming units (CFUs) recovered from macrophages after 24 h of infection was significantly reduced following pre-treatment with the HO-1 Inhibitor zinc (II) protoporphyrin IX (ZnPP, 10 μM) as compared to the solvent-treated control cells (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data
There were no significant differences in lactate dehydrogenase activity between hmox-deficient and control cells with or without Salmonella infection.
“Of note, we found no significant differences between hmox deficient (hmox.sh) and control cells with or without Salmonella infection (Supplementary Figure S3 A)”
Quote in the paperSubstantial claim - Findingown data
IL-10 concentrations did not differ between infected ctrl.sh and hmox.sh macrophages.
“In accordance with the transcriptional analyses, the concentrations of TNF-α, IL-6 and Lcn2 were significantly increased in culture supernatants of hmox.sh cells infected with Salmonella at 20 h post infection as compared to infected control.sh cells (Fig. 5A–C), whereas IL-10 concentrations did not differ between ctrl. sh and hmox.sh macrophages (Figs 5D and 4).”
Quote in the paperNot a substantial claim - Findingown data
Bone marrow-derived macrophages from macrophage-specific HO-1 knockout mice controlled intracellular Salmonella numbers significantly better than control macrophages.
“Following infection with S. Typhimurium we observed significantly better control of intracellular bacterial numbers in macrophage specific HO-1 knockout cells (BMDM) compared with control cells, which confirmed the phenotype observed in RAW.sh cells.”
Quote in the paperSubstantial claim - Findingown data
Concentrations of TNF-α, IL-6, and Lcn2 were significantly increased in culture supernatants of Salmonella-infected hmox.sh cells at 20 h post-infection compared with infected control.sh cells.
“In accordance with the transcriptional analyses, the concentrations of TNF-α, IL-6 and Lcn2 were significantly increased in culture supernatants of hmox.sh cells infected with Salmonella at 20 h post infection as compared to infected control.sh cells (Fig. 5A–C), whereas IL-10 concentrations did not differ between ctrl. sh and hmox.sh macrophages (Figs 5D and 4).”
Quote in the paperSubstantial claim - Findingown data
The high iron flux in hmox knockdown cells resulted in significantly reduced iron acquisition by intracellular Salmonella compared with Salmonella in ctrl.sh macrophages.
“Remarkably, the high iron flux observed in hmox knockdown cells resulted in a significant reduction in iron acquisition by intracellular Salmonella as compared to Salmonella in ctrl.sh macrophages.”
Quote in the paperSubstantial claim - Interpretationown data
hmox gene knockdown results in improved control of infection with intracellular bacteria.
“This study provides evidence that hmox gene knockdown results in improved control of infection with intracellular bacteria.”
Quote in the paperSubstantial claim - Interpretationown data
hmox has a general and early immune de-activating effect in inflammatory macrophages.
“Of note, in comparison to control macrophages an increased expression of tnfa, il6 and lcn2 was also seen in hmox knockdown cells upon treatment with either heat-inactivated Salmonella (Fig. 4) or lipopolysaccharide (data not shown), pointing to a general and early immune de-activating effect of hmox in inflammatory macrophages.”
Quote in the paperSubstantial claim - Interpretationown data
The growth-promoting effect of HO-1 on intramacrophage Salmonella is independent of Nramp1 functionality.
“However, blockade of HO-1 activity by ZnPP resulted in comparable reductions of bacterial numbers in both cell types suggesting that the growth promoting effect of HO-1 towards intramacrophage Salmonella is independent of Nramp1 functionality (Figure S2 B).”
Quote in the paperSubstantial claim - Interpretationown data
The effects of hmox on macrophage antimicrobial activity are dependent on oxidative stress.
“This suggested that the effects of hmox on macrophage antimicrobial activity are dependent on oxidative stress.”
Quote in the paperSubstantial claim - Interpretationown data
Increased TfR1 and reduced ferritin protein levels in hmox knockdown macrophages at baseline and upon Salmonella infection are consistent with reduced intracellular iron concentrations due to increased iron export.
“In addition, the increased TfR1 and reduced ferritin protein levels in hmox knockdown macrophages at baseline and upon Salmonella infection are consistent with reduced intracellular iron concentrations as a consequence of increased iron export (Fig. 2G).”
Quote in the paperSubstantial claim - Premisecitation
Reduction in intracellular iron concentrations promotes production of pro-inflammatory molecules such as TNF-α, IL-6, iNOS, or CCL-20 by activated macrophages.
“Reduction in intracellular iron concentrations has been shown to promote the production of pro-inflammatory molecules such as TNF-α, IL-6, iNOS (nos2) or CCL-20 by activated macrophages (Weiss et al., 1994; Melillo et al., 1997; Ludwiczek et al., 2003; Oexle et al., 2003; Varesio et al., 2010), and these pathways are of importance for the control of intracellular pathogens like Salmonella (Andrews”
Quote in the paperSubstantial claim0 of 3 sources checked - Study design and conductown data
In RAW.sh macrophages treated with 1 μg/ml doxycycline 24-48 h before experiments, the hmox.sh 1 inducible shRNA achieved 94% hmox1 knockdown relative to the luciferase control.
“Inducible shRNA transduction reached 82% (hmox.sh 2) and 94% (hmox.sh 1) hmox1 gene knockdown efficacy—after treatment of the RAW.sh macrophages with 1 μg/ml doxycycline 24–48 h prior to experiments as compared to the luciferase control (ctrl.sh).”
Quote in the paperSubstantial claim - Interpretationreasoning
hmox knockdown limits bacterial iron availability.
“Therefore, hmox knockdown limits bacterial iron availability.”
Quote in the paperSubstantial claim - Interpretationcitation
Bacterial iron limitation in hmox-silenced macrophages is further promoted via increased production of Lcn2, which binds and neutralizes bacterial siderophores.
“Further, bacterial iron limitation in hmox-silenced macrophages is further promoted via increased production of Lcn2 which binds and neutralizes bacterial siderophores (Flo et al., 2004; Berger et al., 2006).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
NF-κB is activated because of a lack of HO-1-derived anti-inflammatory molecules, CO and bilirubin.
“These observations suggest that NF-κB is activated because of a lack of HO-1 derived anti-inflammatory molecules (CO, bilirubin) and is consistent with previous findings showing that the CO releasing compound, CORM-2, inhibits the DNA binding activity of NF-κB resulting in reduced TNFα production (Sawle et al., 2005; Megias et al., 2007; Motterlini et al., 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
HO-1 appears to have a dual role in infections.
“It is important to note, that HO-1 appears to have a dual role in infections.”
Quote in the paperSubstantial claim - Interpretationown data
Increased NF-κB activity is associated with improved anti-microbial immune responses in hmox.sh macrophages.
“We detected increased NF-κB activity in association with improved anti-microbial immune responses in hmox.sh macrophages, which is consistent with NF-kB as a central regulator of inflammatory responses (Tak and Firestein, 2001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tak and Firestein, 2001 source
Not checked in the free run.
- Premisecitation
Hemophagocytic macrophages, which express high levels of HO-1, provide a survival niche for Salmonella.
“This goes along with the observation that hemophagocytic macrophages, which express high levels of HO-1, provide a survival niche for Salmonella (Nix et al., 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nix et al., 2007 source
Not checked in the free run.
- Interpretationcitation
TNF-α produced in larger quantities as a result of hmox silencing further contributes to RNS and ROS production because of co-activation of inos and p47phox expression.
“In addition, TNF-α produced in larger quantities as a result of hmox silencing further contributes to RNS and ROS production because of the co-activation of inos and p47phox expression (Ables et al., 2001).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ables et al., 2001 source
Not checked in the free run.
- Interpretationcitation
Reduced abundance of CO and bilirubin contributes to increased or prolonged oxidative stress because these molecules have radical scavenging and anti-inflammatory activities.
“In addition, the reduced abundance of CO and bilirubin, two end-products of the HO-1 pathway, further contributes to increased or prolonged oxidative stress, as these molecules have radical scavenging capacities and anti-inflammatory activities (Gozzelino et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Gozzelino et al., 2010 source
Not checked in the free run.
- Study design and conductown data
In RAW.sh macrophages treated with 1 μg/ml doxycycline 24-48 h before experiments, the hmox.sh 2 inducible shRNA achieved 82% hmox1 knockdown relative to the luciferase control.
“Inducible shRNA transduction reached 82% (hmox.sh 2) and 94% (hmox.sh 1) hmox1 gene knockdown efficacy—after treatment of the RAW.sh macrophages with 1 μg/ml doxycycline 24–48 h prior to experiments as compared to the luciferase control (ctrl.sh).”
Quote in the paperSubstantial claim - Interpretationreasoning
Increased ROS and RNS production resulting from hmox knockdown enhances immune control of Salmonella.
“Thus, increased ROS and RNS production resulting from hmox knockdown enhances immune control of Salmonella.”
Quote in the paperSubstantial claim
- May combine two claims. 20
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 7
May combine two claims.
Findingown dataIncreased cellular iron export was observed in Salmonella-infected hmox.sh macrophages at 20 h post-infection, although cytoplasmic fpn1 mRNA levels were reduced at this time.
“Increased cellular iron export (Fig. 2C and F) was observed in Salmonella infected hmox.sh macrophages 20 h post-infection, although cytoplasmic ferroportin (fpn1) mRNA levels were reduced at this time.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataROS levels were significantly higher in hmox knockdown than in control cells and were not significantly altered by CORM-2 or bilirubin.
“ROS levels were significantly higher in hmox knockdown than in control cells, which was not significantly altered in the presence of CORM-2 or bilirubin (Fig. S1 B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIntramacrophage numbers of an iron-uptake-deficient Salmonella mutant were still significantly lower upon hmox silencing than in control macrophages, although the difference was less prominent than with wild-type Salmonella.
“Although, the differences in bacterial counts between ctrl.sh and hmox.sh macrophages were less prominent than during infection with wt Salmonella, intramacrophage numbers of mutant Salmonella were still significantly lower upon hmox silencing than in wt macrophages.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Crouch et al., 2008 source
Not checked in the free run.
May combine two claims.
Findingown datatnfa formation was significantly higher in hmox.sh macrophages at early infection time points and then declined, whereas il10 expression did not significantly differ between infected hmox.sh and ctrl.sh macrophages.
“However, whereas tnfa formation was significantly higher in hmox.sh macrophages at early time points of infection and then declined, no significant differences in il10 expression were observed between infected hmox.sh and ctrl.sh macrophages (Fig. 3D and E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIron supplementation significantly increased the bacterial load in both hmox knockdown and ctrl.sh macrophages, increasing intramacrophage bacterial numbers in hmox.sh phagocytes to those observed in control cells.
“Iron supplementation significantly increased the bacterial load in both, hmox knockdown and ctrl.sh macrophages thereby increasing the intramacrophage bacterial numbers in hmox.sh phagocytes to that observed in control cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSalmonella infection significantly increased tfr1 and dmt1 expression, and this increase was significantly higher in hmox.sh than in ctrl.sh cells.
“However, we observed a significant increase in tfr1 and dmt1 expression following infection with S. Typhimurium that was significantly higher in hmox. sh than in ctrl.sh cells (Fig. 2A and B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSilencing hmox in Salmonella-infected macrophages caused significant time-dependent induction of p47phox and nos2 mRNA expression compared with infected control macrophages, and both genes were significantly higher in hmox.sh than control.sh cells at all time points.
“We found that silencing of hmox was paralleled by a significant time-dependent induction of p47 phagocyte oxidase (p47phoX) and inducible nitric oxide synthase (nos2) mRNA expression as compared to infected control macrophages (Fig. 3A and B).”
- Also stated in: § Impact of HO-1 on macrophage effector functions · plain
“However, at all time points, both genes were significantly higher expressed in hmox.sh than in control. sh cells (Fig. 3A and B).”
Quote in the paperSubstantial claim- Also stated in: § Impact of HO-1 on macrophage effector functions · plain
The quote only partly states this claim.
Findingown dataSalmonella-infected hmox.sh cells produced significantly more ROS than analogously treated control.sh macrophages at 30 min and 3 h post-infection.
“Salmonella-infected hmox.sh cells produced significantly more ROS in comparison to the analogously treated crtl.sh macrophages (Fig. 6B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBilirubin addition did not change bacterial numbers in ctrl.sh cells but increased those in hmox.sh macrophages, resulting in an insignificant change of bacterial numbers.
“Addition of bilirubin did not change bacterial numbers in ctrl.sh cells but increased those in hmox.sh macrophages resulting in an insignificant change of bacterial numbers (Figure S1 A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataCORM-2 treatment significantly reduced bacterial numbers in both cell types, but differences between control and hmox knockdown cells remained evident.
“Moreover, CORM-2 treatment significantly reduced bacterial numbers in both cells types (Figure S1 A), but the differences between control and hmox knockdown cells remained evident.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datahmox knockdown macrophages have low iron content and reduced iron pools while expressing significantly higher levels of NF-κB than corresponding control cells.
“However, hmox knockdown macrophages have low iron content and reduced iron pools at the same time expressing significantly higher levels of NF-κB than the corresponding control cells.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe improved control can be attributed to impaired bacterial survival mainly as a consequence of iron limitation for intramacrophage microbes along with stimulation of antimicrobial immune effector pathways including radical formation.
“These can be attributed to impaired bacterial survival, mainly as a consequence of iron limitation for intramacrophage microbes along with stimulation of antimicrobial immune effector pathways including radical formation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFunctional Nramp1 expression in RAW264.7 macrophages is associated with significantly lower intracellular Salmonella multiplication than in macrophages lacking Nramp1 activity.
“As described in the literature the intracellular multiplication of Salmonella was significantly lower in RAW cells expressing the functional Nramp1 than in macrophages lacking Nramp1 activity (Cellier et al, 2007; Fritsche et al, 2012).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationSalmonella cannot utilize heme and requires the hmox breakdown product iron as a growth factor.
“In addition, Salmonella cannot utilize heme and thus requires the hmox breakdown product iron as a growth factor (Andrews-Polymenis et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Andrews-Polymenis et al., 2010 source
Not checked in the free run.
May combine two claims.
Interpretationown dataBacterial iron restriction contributes to impaired bacterial proliferation upon hmox knockdown but is not exclusively responsible for the protective effect.
“This indicated that bacterial iron restriction contributes to impaired bacterial proliferation upon hmox knockdown but is not exclusively responsible for the observed protective effect.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHeme oxygenase 1 is the first and rate-limiting enzyme in heme breakdown, producing equal amounts of iron, carbon monoxide, and biliverdin.
“The enzyme heme oxygenase 1 (HO-1, hmox) is of central importance in this process because it degrades heme to yield equal amounts of iron, carbon monoxide and biliverdin (Tenhunen et al., 1968; Ryter and Tyrrell, 2000).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Tenhunen et al., 1968 source
Not checked in the free run.
- cites Ryter and Tyrrell, 2000
Not checked in the free run.
May combine two claims.
Interpretationown datahmox depletion causes induction of Fpn1-mediated iron efflux, which limits the availability of iron for Salmonella.
“Specifically, our data show that hmox depletion causes an induction of Fpn1-mediated iron efflux (Fig. 2C, E) which limits the availability of iron for Salmonella.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe infection-driven induction of HO-1 exerts detrimental effects in the early control of Salmonella infection, whereas hmox inhibition can favourably modulate anti-bacterial immune effector pathways of macrophages and promote bacterial elimination.
“Taken together our data provide novel evidence that the infection-driven induction of HO-1 exerts detrimental effects in the early control of Salmonella infection, whereas hmox inhibition can favourably modulate anti-bacterial immune effector pathways of macrophages and promote bacterial elimination.”
Quote in the paperSubstantial claim- Rests on an assumption: Infection with Salmonella leads to increased HO-1 expression in host cells.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInhibition of HO-1, especially at early stages of infection, limits intracellular bacterial numbers in Mycobacteria abscessus.
“Furthermore, a recent study of Mycobacteria abscessus found that inhibition of HO-1, especially at the early stages of infection, limits intracellular bacterial numbers (Abdalla et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Abdalla et al., 2015 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe dual role of HO-1 may become most evident in persisting infections; downregulation appears beneficial for immediate control, but in non-resolving infection HO-1 expression at later stages may be necessary to reduce inflammation-driven tissue damage.
“The dual role of HO-1 may thus become most evident in the course of persisting infections. Its downregulation appears to be beneficial for the immediate control of infection with intracellular pathogens, but in non-resolving infection HO-1 expression at later stages may be necessary to reduce inflammation driven tissue damage.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe current study shows that hmox knockdown in macrophages limits bacterial replication by reducing intracellular iron pools and subsequent bacterial iron incorporation along with stimulation of anti-microbial immune effector mechanisms.
“The current study shows that hmox knockdown in macrophages limits bacterial replication by reducing intracellular iron pools and subsequent bacterial iron incorporation along with stimulation of anti-microbial immune effector mechanisms.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe Salmonella triple mutant ΔentCΔsitΔfeo lacks the ability to synthesize enterobactin and to take up iron via SitABCD and Feo.
“The mutant strain, deficient in enterobactin synthesis, SitABCD- and Feo-mediated iron uptake (ΔentCΔsitΔfeo) was constructed and grown as previously described (Crouch et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Crouch et al., 2008 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationHO-1 expression is associated with increased susceptibility to Salmonella bacteremia during malaria infection and increased mortality from Salmonella infection in that setting.
“On the other side of the coin, HO-1 expression is associated with increased susceptibility to Salmonella bacteremia during malaria infection, and increased mortality from Salmonella infection in that setting (Cunnington et al., 2012).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cunnington et al., 2012 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenIn vitro infection assays using RAW264.7 cells stably transfected with hmox1 shRNA or bone marrow-derived macrophages produced comparable results.
“RAW264.7 cells stable transfected with hmox1 shRNA or BMDM were used for in vitro infection assays generating comparable results.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationUp-regulation of HO-1 during malaria or sepsis is associated with infection tolerance and limitation of tissue damage resulting in improved survival.
“Up-regulation of HO-1 during malaria or sepsis was demonstrated in association with infection tolerance and limitation of tissue damage resulting in an improved survival (Gozzelino et al., 2010; Larsen et al., 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checked
The paper relies on this without support.
HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin.
“HO-1 is strongly up-regulated in macrophages in response to inflammatory signals, including bacterial endotoxin.”
The paper relies on this without support.
Infection with Salmonella leads to increased HO-1 expression in host cells.
“Accordingly, infection with Salmonella leads to increased HO-1 expression in host cells, which may be seen as an attempt of the pathogen to weaken host-derived anti-microbial effector pathways and to secure a sufficient supply of iron.”
The paper relies on this without support.
Heat-killed Salmonella serve as a standardized inflammatory trigger whose effect does not depend on the number of bacteria.
“They are used as a defined inflammatory stimulus not compromised by bacterial number.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Free heme, predicted to accumulate when Hmox1 is inhibited, activates NF-κB to induce TNF and Nos2 transcription resulting in improved control of Salmonella infection.
“Accordingly, free heme, which is predicted to accumulate when Hmox1 is inhibited, activates NF-κB to induce TNF and Nos2 transcription resulting in improved control of Salmonella infection [154].”
From “Pumping iron”—how macrophages handle iron at the systemic, microenvironmental, and cellular levels (2017) · cites this paper as [154]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Figure 2E is cited for both iron uptake and iron efflux
MinorThe Results identify Fig. 2E as showing iron uptake and cite Fig. 2F for iron export. The Discussion instead cites Fig. 2E as evidence of iron efflux.
“Specifically, our data show that hmox depletion causes an induction of Fpn1-mediated iron efflux (Fig. 2C, E) which limits the availability of iron for Salmonella.”
“These changes were paralleled by a significant increase in transferrin- bound iron (TBI) and non-transferrin bound iron (NTBI) uptake by uninfected and infected hmox.sh cells as compared to ctrl.sh. (Fig. 2D and E). Increased cellular iron export (Fig. 2C and F) was observed in Salmonella infected hmox.sh macrophages 20 h post-infection”
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NITRIC OXIDE AND MACROPHAGE FUNCTION
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NF-κB: a key role in inflammatory diseases
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Nitric oxide and the immune response
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Heme Oxygenase-1 Expression in Macrophages Plays a Beneficial Role in Atherosclerosis
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Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases
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Self-citationIron and innate antimicrobial immunity-depriving the pathogen, defending the host
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Self-citationHeme Oxygenase-1 as a Modulator of Intestinal Inflammation Development and Progression
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Self-citationMolecular Mechanisms Used by Salmonella to Evade the Immune System
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Malaria, anemia, and invasive bacterial disease: A neutrophil problem?
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Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases
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- Authors
- Mitterstiller, A.-M., Haschka, D., Dichtl, S., Nairz, M., Demetz, E., Talasz, H., Soares, M. P., Einwallner, E., Esterbauer, H., Fang, F. C., Geley, S., & Weiss, G.
- Affiliations
- Innsbruck Medical University (AT)
- Instituto Gulbenkian de Ciência (PT)
- Medical University of Vienna (AT)
- University of Washington (US)
- Department of Internal Medicine VI, Infectious Diseases, Immunology, Rheumatology, Pneumology; Medical University of Innsbruck; 6020 Innsbruck Austria
- ORCID
- Venue
- Cellular Microbiology
- Publisher
- Hindawi Limited
- Published
- 2016-03-18
- Volume
- 18
- Issue
- 10
- Pages
- 1374-1389
- ISSN
- 1462-5814 (ISSN-L)
- PMC
- PMC6557132
- OpenAlex
- W2266696487
- Cited by
- 62
- References
- 95
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 12 · 2017: 9 · 2016: 3
- FWCI
- 5.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cellular Microbiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Austrian Research Fund (FWF)
- Verein zur Förderung von Forschung und Weiterbildung in Infektiologie und Immunologie an der Medizinischen Universität Innsbruck
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- heme oxygenase-1, Salmonella typhimurium, macrophages, innate immunity, iron limitation, intracellular bacterial survival, NF-κB activation, reactive oxygen species, reactive nitrogen species, TNF-α, carbon monoxide, biliverdin, shRNA knockdown, NRAMP1, phagocytosis
- MeSH terms
- RAW 264.7 Cells, Animals, Enzyme Induction, Humans, Immunity, Innate, Iron, Membrane Proteins, Salmonella Infections, Salmonella typhimurium, Gene Expression, NF-kappa B, Reactive Oxygen Species, Microbial Viability, Mice, Heme Oxygenase-1, HEK293 Cells
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