Cellular iron governs the host response to malaria infection and vaccination

Iron deficiency and malaria are two major public health problems with largely overlapping epidemiology, and there is a complex relationship between iron and malaria. Iron deficiency can protect from malaria infection, whereas iron supplementation can increase the risk, and tissue iron loading can disrupt disease tolerance. Immune cells also need iron to support their function and iron deficiency can disrupt immunity. However, it is not known how tolerance or the immune response to malaria infection and vaccination is affected by iron deficiency. In this thesis, the effects of cellular iron deficiency on the host’s response to malaria infection and vaccination were investigated. Recently mosquito transmitted P. chabaudi parasites were used to infect mice with a mutation in transferrin receptor 1 (TfrcY20H/Y20H mice), which causes decreased cellular iron uptake. We discovered that TfrcY20H/Y20H mice had higher P. chabaudi parasite burden, but comparable malaria induced anaemia. The disease phenotype of TfrcY20H/Y20H mice was also altered, as they had increased weight loss and exacerbated kidney damage, but attenuated liver damage compared to wild-type mice. In addition, disrupted cellular iron uptake had a range of inhibitory effects on the immune response to P. chabaudi. The expansion of key effector cells was reduced during the acute stage of infection and the germinal centre response was impaired in TfrcY20H/Y20H mice. Moreover, TfrcY20H/Y20H lymphocytes cultured in vitro had impaired proliferation and effector function, which could be completely rescued by iron supplementation. We also demonstrated that decreased cellular iron uptake weakened the immune response to blood-stage malaria vaccine RH5.1 and that mini-hepcidin induced hypoferremia disrupted the response to experimental liver-stage vaccine AdHu5-Py9. Hence, we have demonstrated for the first time that cellular iron deficiency has the potential to alter malaria disease tolerance and to impair the immune response to malaria infection and vaccination

Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL‐10

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte‐specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti‐inflammatory energy substrates. Instead, Atg7‐deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2‐mediated upregulation of Ephx1. This shift reduced secretion of IL‐10 from adipose tissues, which was dependent on the cytochrome P450‐EPHX pathway, and lowered circulating levels of IL‐10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat‐gut crosstalk through an autophagy‐dependent regulation of anti‐inflammatory oxylipins via the cytochrome P450‐EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation

Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL‐10

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation