Innate Immune System Essential Component

The innate immune system in fish is an essential component in the fight against pathogenic agents. In contrast, the adaptive immune system is limited in fish due to being poikilothermic, having a restricted repertoire of antibodies, and presenting low lymphocyte proliferation, maturation, and memory. The cells and molecules of the innate immune system use non-clonal pattern recognition receptors, such as lectins, Toll-like receptors, and NOD-like receptors. These receptors not only recognize molecular structures essential for microorganism survival/pathogenicity but also allow the innate immune response to rapidly respond to control pathogen growth and promote inflammation and adaptive immunity mechanisms. Under inflammation and/or infestation conditions, the innate immune system induces various antimicrobial mechanisms, such as depleting the iron available to pathogens at the systemic and cellular levels. This defense mechanism, known as nutritional immunity or iron withholding, consists in the removal of this nutrient from circulation and posterior sequestration within cells. Proinflammatory cytokines, such as IL-6, stimulate the transcriptional upregulation of hepcidin, triggering and potentiating the hypoferric response of inflammation. In eukaryotic cells and most prokaryotic organisms, iron is needed for survival and proliferation. This necessity arises as iron is a constituting element of hemoproteins, the iron-sulfur protein (Fe-S), and proteins that use iron in other functional groups to carry out essential functions of cellular metabolism. In fish, the iron preferentially crosses the apical membrane of gills and intestine in ferrous state by the divalent metal transporter. Once inside the cell, iron can be stored in the cytoplasmic ferritin (i.e., iron that is not needed for immediate use) sent toward the mitochondria (i.e., Fe-S cluster biogenesis or heme synthesis), or be used in other iron pathways. Cellular iron export is regulated by hepcidin and ferroportin, the binding of both proteins leads the internalization and degradation of ferroportin. Ferroportin is responsible for iron transfer from the basolateral membrane of the cell to the blood but iron export also depends on the presence of an associated copper, such as hephaestin (implicated in intestinal iron transport) and ceruloplasmin (implicated in the iron export from non-intestinal cells). This ferroxidase allows iron to be carried in the cytoplasmic transferrin and be sent to another tissue. Cellular iron uptake can occur through transferrin receptor 1 (TfR1), which is ubiquitously expressed in tissues or through TfR2, a homologous receptor of TfR1 that is found in hepatic duodenal crypt cells and erythroid cells, localizations suggestive of a more specialized role for this receptor in iron metabolism.

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Alex John
Editorial Assistant
Immunotherapy Open Access