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Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet-induced obesity

View Article: PubMed Central - PubMed

ABSTRACT

Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high-fat diet-induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil- and macrophage-based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi-infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high-fat diet, toll-like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow-derived macrophages from obese, B. burgdorferi-infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice.

No MeSH data available.


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Infection-dependent global suppression of macrophage cytokine production in response to Borrelia burgdorferi challenge in diet-induced obesity (DIO). Cytokines produced ex vivo by peritoneally recruited macrophages from male C3H/HeN mice 1 and 8 weeks after mice were inoculated with cultivation medium alone (mock) or 1 × 104 GCB726 (infected). (a) Global induction of all cytokines by co-incubation with B. burgdorferi, normalized to basal cytokine production by unstimulated PMs from age-matched normal diet (ND) mock-infected mice. (b–c) Global high-fat diet (HFD):ND fold-difference/cytokine for all cytokines, unadjusted (b) and adjusted (c) for differences in B. burgdorferi uptake efficiency among groups (Figure 5c). (d–e) HFD:ND fold-differences for individual cytokines at 1 (d) and 8 (e) weeks. (f–g) Pro-inflammatory: anti-inflammatory (tumor necrosis factor [TNF]α:interleukin [IL]-10) cytokine ratios for individual mice at 1 (f) and 8 (g) weeks post-inoculation. Raw data for all panels are provided in Figure S7. N ≥ 12 mice per diet group and time point. Data summaries: mean ± standard error of the mean (SEM). * indicates p < 0.05 HFD versus ND within infection group and time point. † indicates p < 0.05 infected versus mock. # indicates p < 0.05 8 versus 1 week within infection group. ^ indicates p < 0.05 versus age-matched ND mock group
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Figure 6: Infection-dependent global suppression of macrophage cytokine production in response to Borrelia burgdorferi challenge in diet-induced obesity (DIO). Cytokines produced ex vivo by peritoneally recruited macrophages from male C3H/HeN mice 1 and 8 weeks after mice were inoculated with cultivation medium alone (mock) or 1 × 104 GCB726 (infected). (a) Global induction of all cytokines by co-incubation with B. burgdorferi, normalized to basal cytokine production by unstimulated PMs from age-matched normal diet (ND) mock-infected mice. (b–c) Global high-fat diet (HFD):ND fold-difference/cytokine for all cytokines, unadjusted (b) and adjusted (c) for differences in B. burgdorferi uptake efficiency among groups (Figure 5c). (d–e) HFD:ND fold-differences for individual cytokines at 1 (d) and 8 (e) weeks. (f–g) Pro-inflammatory: anti-inflammatory (tumor necrosis factor [TNF]α:interleukin [IL]-10) cytokine ratios for individual mice at 1 (f) and 8 (g) weeks post-inoculation. Raw data for all panels are provided in Figure S7. N ≥ 12 mice per diet group and time point. Data summaries: mean ± standard error of the mean (SEM). * indicates p < 0.05 HFD versus ND within infection group and time point. † indicates p < 0.05 infected versus mock. # indicates p < 0.05 8 versus 1 week within infection group. ^ indicates p < 0.05 versus age-matched ND mock group

Mentions: Finally, we determined if the ability of macrophages to produce cytokines in response to B. burgdorferi challenge ex vivo was also cooperatively suppressed by B. burgdorferi infection and DIO. After 1 week of B. burgdorferi infection, global B. burgdorferi-elicited cytokine production by PMs from both mock and infected HFD groups was significantly impaired compared to ND groups (Figure 6a–b). However, after 8 weeks of infection, DIO and B. burgdorferi infection alone independently enhanced B. burgdorferi-responsive cytokine production compared to age-matched ND mock controls, whereas DIO and B. burgdorferi infection together suppressed this response (Figure 6a–b). This effect was primarily due to reduced bacterial uptake efficiency in macrophages from infected HFD mice, because B. burgdorferi-elicited global cytokine production in these cells was not impaired compared to ND controls after adjustment for differences in uptake efficiency (Figure 6c). At 1 week post-inoculation, production of 44% and 81% of individual cytokines was attenuated in HFD compared to ND groups for mock and B. burgdorferi-infected mice, respectively (Figure 6d). By contrast, at 8 weeks post-inoculation, 0% of individual cytokines were attenuated in HFD versus ND groups for mock-infected animals, whereas in B. burgdorferi-infected mice production of 75% of cytokines was attenuated in HFD compared to ND animals (Figure 6e). As for serum cytokines (Figure 4i), cytokine production by macrophages from infected HFD mice at both 1 and 8 weeks post-infection was significantly less pro-inflammatory than cytokine production by macrophages from infected ND mice (Figure 6f–g), due to reduced TNF-α production, but not increased IL-10 secretion (Figure 6d–e). Therefore, B. burgdorferi infection and DIO cooperatively suppressed macrophage cytokine production in response to B. burgdorferi, and this effect became more pronounced as infection progressed.


Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet-induced obesity
Infection-dependent global suppression of macrophage cytokine production in response to Borrelia burgdorferi challenge in diet-induced obesity (DIO). Cytokines produced ex vivo by peritoneally recruited macrophages from male C3H/HeN mice 1 and 8 weeks after mice were inoculated with cultivation medium alone (mock) or 1 × 104 GCB726 (infected). (a) Global induction of all cytokines by co-incubation with B. burgdorferi, normalized to basal cytokine production by unstimulated PMs from age-matched normal diet (ND) mock-infected mice. (b–c) Global high-fat diet (HFD):ND fold-difference/cytokine for all cytokines, unadjusted (b) and adjusted (c) for differences in B. burgdorferi uptake efficiency among groups (Figure 5c). (d–e) HFD:ND fold-differences for individual cytokines at 1 (d) and 8 (e) weeks. (f–g) Pro-inflammatory: anti-inflammatory (tumor necrosis factor [TNF]α:interleukin [IL]-10) cytokine ratios for individual mice at 1 (f) and 8 (g) weeks post-inoculation. Raw data for all panels are provided in Figure S7. N ≥ 12 mice per diet group and time point. Data summaries: mean ± standard error of the mean (SEM). * indicates p < 0.05 HFD versus ND within infection group and time point. † indicates p < 0.05 infected versus mock. # indicates p < 0.05 8 versus 1 week within infection group. ^ indicates p < 0.05 versus age-matched ND mock group
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Figure 6: Infection-dependent global suppression of macrophage cytokine production in response to Borrelia burgdorferi challenge in diet-induced obesity (DIO). Cytokines produced ex vivo by peritoneally recruited macrophages from male C3H/HeN mice 1 and 8 weeks after mice were inoculated with cultivation medium alone (mock) or 1 × 104 GCB726 (infected). (a) Global induction of all cytokines by co-incubation with B. burgdorferi, normalized to basal cytokine production by unstimulated PMs from age-matched normal diet (ND) mock-infected mice. (b–c) Global high-fat diet (HFD):ND fold-difference/cytokine for all cytokines, unadjusted (b) and adjusted (c) for differences in B. burgdorferi uptake efficiency among groups (Figure 5c). (d–e) HFD:ND fold-differences for individual cytokines at 1 (d) and 8 (e) weeks. (f–g) Pro-inflammatory: anti-inflammatory (tumor necrosis factor [TNF]α:interleukin [IL]-10) cytokine ratios for individual mice at 1 (f) and 8 (g) weeks post-inoculation. Raw data for all panels are provided in Figure S7. N ≥ 12 mice per diet group and time point. Data summaries: mean ± standard error of the mean (SEM). * indicates p < 0.05 HFD versus ND within infection group and time point. † indicates p < 0.05 infected versus mock. # indicates p < 0.05 8 versus 1 week within infection group. ^ indicates p < 0.05 versus age-matched ND mock group
Mentions: Finally, we determined if the ability of macrophages to produce cytokines in response to B. burgdorferi challenge ex vivo was also cooperatively suppressed by B. burgdorferi infection and DIO. After 1 week of B. burgdorferi infection, global B. burgdorferi-elicited cytokine production by PMs from both mock and infected HFD groups was significantly impaired compared to ND groups (Figure 6a–b). However, after 8 weeks of infection, DIO and B. burgdorferi infection alone independently enhanced B. burgdorferi-responsive cytokine production compared to age-matched ND mock controls, whereas DIO and B. burgdorferi infection together suppressed this response (Figure 6a–b). This effect was primarily due to reduced bacterial uptake efficiency in macrophages from infected HFD mice, because B. burgdorferi-elicited global cytokine production in these cells was not impaired compared to ND controls after adjustment for differences in uptake efficiency (Figure 6c). At 1 week post-inoculation, production of 44% and 81% of individual cytokines was attenuated in HFD compared to ND groups for mock and B. burgdorferi-infected mice, respectively (Figure 6d). By contrast, at 8 weeks post-inoculation, 0% of individual cytokines were attenuated in HFD versus ND groups for mock-infected animals, whereas in B. burgdorferi-infected mice production of 75% of cytokines was attenuated in HFD compared to ND animals (Figure 6e). As for serum cytokines (Figure 4i), cytokine production by macrophages from infected HFD mice at both 1 and 8 weeks post-infection was significantly less pro-inflammatory than cytokine production by macrophages from infected ND mice (Figure 6f–g), due to reduced TNF-α production, but not increased IL-10 secretion (Figure 6d–e). Therefore, B. burgdorferi infection and DIO cooperatively suppressed macrophage cytokine production in response to B. burgdorferi, and this effect became more pronounced as infection progressed.

View Article: PubMed Central - PubMed

ABSTRACT

Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high-fat diet-induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil- and macrophage-based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi-infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high-fat diet, toll-like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow-derived macrophages from obese, B. burgdorferi-infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice.

No MeSH data available.


Related in: MedlinePlus