Iron is an essential element for virtually all cell types due to its role in energy metabolism, nucleic acid synthesis and cell proliferation. Nevertheless, if free, iron induces cellular and organ damage through the formation of free radicals. Thus, iron levels must be firmly controlled. During infection, both host and microbe need to access iron and avoid its toxicity. Alterations in serum and cellular iron have been reported as important markers of pathology. In this regard, ferritin, first discovered as an iron storage protein, has emerged as a biomarker not only in iron-related disorders but also in inflammatory diseases, or diseases in which inflammation has a central role such as cancer, neurodegeneration or infection. The basic research on ferritin identification and functions, as well as its role in diseases with an inflammatory component and its potential as a target in host-directed therapies, are the main considerations of this review.

Mice genetically deficient in the inducible NO synthase gene (iNOS−/−) were used to study the role played by NO during infection by Mycobacterium avium. iNOS−/− macrophages were equally able to restrict M. avium growth in vitro following stimulation by IFN-γ and TNF-α as macrophages from wild-type mice. In vivo, the infection progressed at similar rates in wild-type and NO-deficient mice during the first 2 mo of infection, but the latter mice were subsequently more efficient in clearing the mycobacteria than the former. The increased resistance of iNOS−/− mice was associated with higher IFN-γ levels in the serum and following in vitro restimulation of spleen cells with specific Ag, increased formation of granulomas and increased survival of CD4+ T cells. We show that NO is not involved in the antimycobacterial mechanisms of M. avium-infected macrophages and, furthermore, that it exacerbates the infection by causing the suppression of the immune response to the pathogen.

Heme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1 isoform, encoded by theHmox1gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in macrophages (Mϕ) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1^−/−) mice are more susceptible to intravenousMycobacterium aviuminfection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type (Hmox1^+/+) controls. Furthermore,Hmox1^−/−mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection withMycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed inM. avium-infectedHmox1^−/−versusHmox1^+/+SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected Mϕ, an effect mimicked by exogenous heme administration toM. avium-infected wild-type Mϕin vitroor to micein vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in Mϕ, contributing critically to host resistance toMycobacteriuminfection.

In the mouse, the progression of the Mycobacterium avium infection is highly dependent on the Nramp1 gene. Strains of mice that express the Nramp1^D169 allele are highly susceptible to M. avium infections, while Nramp1^G169 strains of mice can control them. Recently, the Nramp1 gene has been cloned and characterized as coding a transmembrane protein, probably involved in divalent cation transport. One possible function of this protein could be the transport of iron out of the parasite‐harbouring phagosome. Previous work in our lab has shown both in vitro (in macrophage cultures) and in vivo, that the growth rate of M. avium is highly dependent on the amount of iron available in the system. To try to correlate this with the Nramp1 gene function, BALB/c (susceptible) and C.D2 (resistant) congenic mice were treated for 20 days with different doses of iron‐dextran, so as to induce different degrees of iron overload, and infected with M. avium 2447. Iron administration increased M. avium growth in infected organs in a dose‐dependent manner at the same time as it decreased the difference in mycobacterial growth between the two mouse strains. These results indicate that an excess of iron hampers Nramp1‐encoded function, strongly suggesting a direct involvement of the Nramp1‐encoded protein in the transport of this cation.

Macrophages are central cells both in the immune response and in iron homeostasis. Iron is both essential and potentially toxic. Therefore, iron acquisition, transport, storage, and release are tightly regulated, by several important proteins. Cytosolic ferritin is an iron storage protein composed of 24 subunits of either the L- or the H-type chains. H-ferritin differs from L-ferritin in the capacity to oxidize Fe²⁺ to Fe³⁺. In this work, we investigated the role played by H-ferritin in the macrophages’ ability to respond to immune stimuli and to deal with exogenously added iron. We used mice with a conditional deletion of the H-ferritin gene in the myeloid lineage to obtain bone marrow-derived macrophages. These macrophages had normal viability and gene expression under basal culture conditions. However, when treated with interferon-gamma and lipopolysaccharide they had a lower activation of Nitric Oxide Synthase 2. Furthermore, H-ferritin-deficient macrophages had a higher sensitivity to iron-induced toxicity. This sensitivity was associated with a lower intracellular iron accumulation but a higher production of reactive oxygen species. These data indicate that H-ferritin modulates macrophage response to immune stimuli and that it plays an essential role in protection against iron-induced oxidative stress and cell death.

Bone homeostasis, based on a tight balance between bone formation and bone degradation, is affected by infection. On one hand, some invading pathogens are capable of directly colonizing the bone, leading to its destruction. On the other hand, immune mediators produced in response to infection may dysregulate the deposition of mineral matrix by osteoblasts and/or the resorption of bone by osteoclasts. Therefore, bone loss pathologies may develop in response to infection, and their detection and treatment are challenging. Possible biomarkers of impaired bone metabolism during chronic infection need to be identified to improve the diagnosis and management of infection-associated osteopenia. Further understanding of the impact of infections on bone metabolism is imperative for the early detection, prevention, and/or reversion of bone loss. Here, we review the mechanisms responsible for bone loss as a direct and/or indirect consequence of infection.