AJCN. First published ahead of print October 25, 2017 as doi: 10.3945/ajcn.117.155838.

Impact of chronic and acute inflammation on extra- and intracellular

iron homeostasis
A Catharine Ross

Department of Nutritional Sciences, Pennsylvania State University, University Park, PA

ABSTRACT important challenges, and opportunities, in understanding how

Inflammation has a major impact on iron homeostasis. This review inflammation per se and the plasma biomarkers of inflammation
focuses on acute and chronic inflammation as it affects iron traffick- used clinically are related to iron homeostasis and its indicators
ing and, as a result, the availability of this essential micronutrient to in both iron-sufficient and iron-depleted populations. This re-
the host. In situations of microbial infection, not only the host is af- view was developed to support discussions that took place
fected but also the offending microorganisms, which, in general, not during the NIH workshop.
only require iron for their own growth but have evolved mechanisms
to obtain it from the infected host. Key players in mammalian iron
trafficking include several types of cells important to iron acquisition,
homeostasis, and hematopoiesis (enterocytes, hepatocytes, macro- CELLS INVOLVED IN IRON HOMEOSTASIS
phages, hematopoietic cells, and in the case of pregnancy, placental Because there is no excretory route, iron homeostasis in or-
syncytiotrophoblast cells) and several forms of chaperone proteins, ganisms is regulated at the level of iron uptake (6). Most iron is
including, for nonheme iron, the transport protein transferrin and the absorbed by enterocytes in the upper small intestine (duodenum).
intracellular iron-storage protein ferritin, and for heme iron, the Iron is taken up at the apical surface mainly through the me-
chaperone proteins haptoglobin and hemopexin. Additional key diation of divalent metal-ion transport proteins; this process is
players are the cell membrane–associated iron transporters, partic- considered to be relatively unregulated. Within the intestinal
ularly ferroportin (FPN), the only protein known to modulate iron absorptive cell, iron can be trafficked to different subcellular
export from cells, and finally, the iron-regulatory hormone hepcidin, compartments (e.g., to ferritin), but the net absorptive process
which, in addition to having antibacterial activity, regulates the depends on the export of iron by ferroportin (FPN) (7), a channel
functions of FPN. Interestingly, the impact of infection on iron protein of the solute carrier family (SLC40A1) on the basolateral
homeostasis differs among pathogens whose mode of infection is
membrane through which ferrous iron exits, to be oxidized ex-
mainly intracellular or extracellular. Understanding how inflamma-
tracellularly to ferric iron by a ferroxidase, and thus prepared for
tion affects each of these processes may be crucial for understanding
binding to the high-affinity binding sites of its plasma transport
how inflammation affects iron status, indicators of iron sufficiency,
protein, transferrin. The importance of FPN is exemplified by
and iron supplementation during inflammation and how it may poten-
the embryonic lethality of the FPNnull/null knockout mouse (8).
tially result in a beneficial or detrimental impact on the host. Am J
More will be said later about the regulation of the process of iron
Clin Nutr doi: https://doi.org/10.3945/ajcn.117.155838.
export by hepcidin and the impact of inflammation on the export
Keywords: acute phase response, C-reactive protein, ferroportin,
of intracellular iron. In general, iron supplementation is ex-
hepatocyte, hepcidin, infancy, intra- and extracellular pathogens, pected, in a mass action manner, to increase the uptake of iron at
macrophage, pregnancy the apical surface, and thus the intracellular ferritin-bound iron
content; however, just how much iron leaves the enterocyte will
depend on the quantity of FPN protein available for iron export.
INTRODUCTION
Presented at the workshop “Iron Screening and Supplementation in Iron-
Inflammation is now recognized as a significant contributor, Replete Pregnant Women and Young Children” held by the NIH Office of
even a causal agent, in chronic metabolic diseases. The in- Dietary Supplements, Bethesda, MD, 28–29 September 2016.
flammatory response results in significant modifications to Supported by NIH HD-066982 and DK-41479 and a Dorothy Foehr Huck
nutrient transport, tissue distribution, and cellular metabolism Endowment.
(1, 2). There is no doubt that inflammation has a significant Address correspondence to ACR (e-mail: [email protected]).
Abbreviations used: AGP, a1-acid glycoprotein; AP, acute phase; APR,
impact on iron homeostasis; however, the mechanisms are far
acute phase response; CRP, C-reactive protein; FPN, ferroportin; HAMP,
less clear. Current evidence has provided important clues, hepcidin antimicrobrial peptide; HO-1, heme oxygenase 1; RBC, red blood
namely concerning the importance of the hepcidin-ferroportin cell; SAA, serum amyloid protein.
axis (3), and the competition that exists between the mammalian doi: https://doi.org/10.3945/ajcn.117.155838.
host and infectious microbes for iron (4, 5). There are still

Am J Clin Nutr doi: https://doi.org/10.3945/ajcn.117.155838. Printed in USA. Ó 2017 American Society for Nutrition 1S of 7S

Copyright (C) 2017 by the American Society for Nutrition

2S of 7S ROSS

Iron that is not exported from the enterocytes can be expected to response generally begins locally and represents a highly evo-
be eliminated in sloughed cells (7). lutionarily conserved program of reactions related to innate
Other cells involved in iron homeostasis include tissue-resident immunity, which are relatively “hard wired” (i.e., modifiable but
macrophages (9) in the splenic red pulp and liver, which together not preventable). The acute response to infection and in-
comprise most of the reticuloendothelial system. Approximately flammation is closely related to immune defense, wound heal-
80% of liver-resident macrophages (Kupffer cells) line the hepatic ing, and tissue repair. Key features are the recruitment of white
venous sinusoids (10). Macrophages are crucial to the recycling of blood cells to the site of injury, through chemotactic and other
iron obtained from catabolism of spent red blood cells (RBCs), and mechanisms, and release of proinflammatory cytokines and
recycling is crucial to maintain a normal rate of RBC formation, chemokines, among which the TNF, IL-1, IL-6, and interferon
and thus for the prevention of anemia (9). Macrophages also store (IFN) families of proteins are predominant or most studied.
excess iron—for example, in situations of unrestrained iron ab- These proteins function as signals that initiate changes in me-
sorption from the diet, as in hereditary hemochromatosis (11). tabolism (19), which include the hepatic acute phase response
Moreover, tissue macrophages are, as will be noted later, also (APR). The APR, as its name implies, is a very rapid response
reservoirs for several intracellular pathogens and, furthermore, initiated by the insult and, optimally, sufficiently strong to deal
intimately involved in the innate immune response through the with the injury or infection, and then to be resolved back to
production of inflammatory factors. Hematopoietic cells in “baseline” homeostatic conditions. Although chronic inflam-
splenic and bone marrow use iron but may be inadequately sup- mation may begin locally, it is characterized by persistence over
plied in states of inflammation, leading to the anemia of in- time, dissemination, and failure to become completely resolved
flammation or anemia of chronic disease (12, 13). Finally, in or quelled, and is thus described as chronic, which implies a
pregnancy, the syncytiotrophoblast cells of the placenta, which survivable, long-term state that is sometimes referred to as “low
interface between the maternal and fetal circulations, function in grade” or mild inflammation.
iron homeostasis and fetal development by transferring iron de- The classical medical description of inflammation includes the
rived from maternal transferrin vectorially across the cell, which cardinal signs: pain, heat, redness, and swelling (i.e., dolor,
is released on the fetal side by a similar mechanism as occurs in caldor, rubor, turgor). The term “inflammation” as it is often
enterocytes involving FPN; however, in this situation, the ex- meant or inferred in relation to chronic diseases is harder to
ported iron becomes bound after oxidation to ferric iron to fetal define, because the origins of the condition itself are less clear.
transferrin. Maternal-to-fetal iron transfer is greatest in the third In fact, side-by-side comparisons between models of acute and
trimester of pregnancy, concomitant with the greatest rate of fetal chronic inflammation are scarce, and the use of the same term,
growth (14). inflammation, for both of them may mask differences yet to be
appreciated. Thus, although it seems safe to say that their gen-
eral features are similar, more research is needed to compare and
PROTEINS INVOLVED IN IRON HOMEOSTASIS elucidate them.
Free iron is toxic due to its participation in un- or poorly Chronic inflammation may result, instead of from acute injury,
regulated cellular and extracellular redox reactions (15), in- from metabolic disturbances, such as long-term tissue damage
cluding the well-known Fenton (Haber-Weiss) reaction in which such as caused by hypoxia, cell death, cellular necrosis, or
hydrogen peroxide and ferrous salts generate reactive species autophagy, arthritis, and other autoimmune disorders, or from
(free radicals) capable of oxidizing a wide variety of organic other nonacute injuries that also result in the recruitment of
substrates (16). Thus, biological mechanisms to bind and se- phagocytic and immune cells and in the production of proin-
quester iron are essential for controlling oxidant production and, flammatory cytokines. Conditions that have now become com-
hence, natural and induced oxidative damage. Nonheme iron is mon in the general population, such as obesity, are linked to
sequestered and transported in plasma by transferrin, which increased inflammation (20), which may be chronic and “low
possesses 2 high-affinity binding sites for 1 atom each of ferric grade” compared with the inflammation of acute infection;
iron. Heme iron, in addition to being contained within RBCs in nonetheless, the body’s pool of metabolically active adipose
hemoglobin, is bound extracellularly by the plasma protein tissue is large, and the inflammation-related cytokines and adi-
haptoglobin, whereas “free” heme is bound intracellularly to pokines produced therein are in intimate contact with other
hemopexin. These proteins function to limit the concentration of tissues through endocrine and paracrine interactions (21).
free inorganic iron and heme-bound iron within the extracellular
space, within cells, or both. Heme has been described as “a
double-edged sword” (17). In moderate quantities and bound to IMPORTANCE OF THE LIVER IN THE APR
protein, it is essential; in large amounts and free, it can become The APR, described .8 decades ago by Tillet and Francis
toxic by mediating oxidative stress and inflammation. Heme (see reference 10), is a highly conserved process found in all
toxicity underlies much of the pathology of sepsis and several mammals (19, 22–25). When infectious agents or their invoked
hemolytic disorders (18). cytokines enter the systemic circulation (sepsis or sterile in-
flammation with an elevation of proinflammatory cytokines), the
liver becomes a central organ of the inflammatory APR, which
ACUTE AND CHRONIC INFLAMMATION AND ITS IM- can be attributed to the following several features of the liver:
PACT ON IRON TRAFFICKING
1) Its anatomical location between the gut and other viscera.
Acute inflammation is part of the body’s natural response to
infection or injury and can rightly be considered an adaptive 2) Its dual venous blood supply, including the portal vein
response, as long as it remains within healthy limits. The through which the liver obtains intestinally derived
 INFLAMMATION AND IRON HOMEOSTASIS 3S of 7S
materials, including microbes that have breached the in-
testinal epithelial barrier, immune cells educated in the
environment of the intestine (including and differing in
the lamina propria, intraepithelial lymphocyte compart-
ment, and specialized gut-associated lymphoid tissue)
(26), and a host of nutritional and other factors including
water-soluble nutrients, food-borne and absorbed toxins,
and cytokines produced in the intestine. Of note, the in-
testine is the body’s largest reservoir of immune cells (27),
including tolerogenic T lymphocytes, and others with in-
flammatory potential (26, 28). Interestingly, the composi-
tion of these cells differs in neonatal and adult life, with
few epithelial T cells in neonates (29). Nevertheless, at all
ages, the portal vein connects a major component of the
body’s innate and adaptive immune system (intestine,
spleen, and pancreas) with the liver (30).
3) The proximity of the apical surface of hepatocytes to the
venous sinusoids, separated only by loose, fenestrated en- FIGURE 1 Schematic of pathway from initial insult to the induction of
dothelial cells, such that these cells readily filter and take the AP response. See Kilicarslan et al. (24) and Trautwein et al. (31) for
up blood-borne materials. reviews of AP proteins. AGP, a1-acid glycoprotein; AP, acute phase; CRP,
C-reactive protein; IFN, interferon.
4) The intrinsic functions of the hepatocytes in central energy
metabolism, including glucose utilization and fatty acid the chaperone proteins haptoglobin and hemopexin, and the
transport. Thus, the utilization of all 3 major fuel sources intracellular iron chelator ferritin, which is also present in small
becomes altered during the APR, which can be considered amounts in plasma, all of which are induced in the APR (24).
a means to redistribute building blocks for tissue repair at Although few reviews of AP proteins have, until recently, listed a
sites of injury, at the (temporary) expense of normal he- sixth factor, hepcidin, it should now be considered an important
patic metabolism, in ways that provide an advantage to AP protein with regard to iron homeostasis (10). As discussed
host survival. further below, the APR affects the distribution of iron to cells
5) Hepatic synthesis of most of the plasma proteins. throughout the body and has significant implications for the
availability of iron to the host and to microbes in the case of
It is this latter function, specifically protein synthesis, that most infectious diseases.
research on the APR and acute phase (AP) proteins has addressed.
Human AP proteins, which number .180, include proteins of
the complement system, coagulation factors, antiproteases, REGULATION OF THE SYNTHESIS OF HEPATIC AP
transport proteins, and inflammatory response proteins (19). PROTEINS
Most of the AP proteins are induced during inflammation and It has become traditional to categorize AP proteins as either
many of them exert crucial effector functions—for example, in class I AP genes, exemplified by CRP, haptoglobin, SAA,
the regulation of blood clotting and as opsonins (24). The best- complement C3, hemopexin, haptoglobin, and AGP (10, 31),
known biomarker of inflammation, C-reactive protein (CRP), which are mainly regulated by IL-1 or by combinations of IL-1
named for its role in reacting to the C-polysaccharide component plus IL-6 or IL-1, IL-6, and glucocorticoids, and class II genes,
of Streptococcus pneumoniae, is an opsonic protein. Several exemplified by a2-macroglobulin, a1-antichymotrypsin, a1-
major AP proteins, considered to be markers of inflammation, antitrypsin, and fibrinogen, for which IL-6 and glucocorticoids
are noted in Figure 1. In humans, CRP and serum amyloid are the major inducers (31). However, current studies have
protein (SAA) are the most prominent responding proteins, with shown that the situation is likely more complex, involving dif-
increases of #100-fold during inflammation. In the rat, a2- ferential regulation by multiple factors. IL-1 and IL-6 still
macroglobulin and al-acid glycoprotein (AGP) are most prom- function as lead regulators, but the APR is further shaped by
inent (31). Although each AP protein exhibits changes in its hormones and other regulatory factors in a manner determined
concentration in plasma after the induction of the APR, the by different inflammatory stimuli (10). The IL-1 family
magnitude and duration of response differ among them; CRP proteins (IL-1b being the most studied) may be the most com-
and SAA proteins are induced very rapidly and to very high con- plex, with both inductive and inhibitory activity (10). IL-1 gen-
centrations after exposure to an inflammatory stimulus, whereas erally signals via pathways that lead to the induction of the
haptoglobin and fibrogen, for example, increase less rapidly and nuclear transcription factor kB, a major regulator of proin-
dramatically (23). Albumin, a major regulator of oncotic pres- flammatory signaling (31). IL-6, originally identified as a B cell
sure, and transferrin as well as several other nutrient transport differentiation factor, is a multifunctional cytokine whose de-
proteins are negative AP proteins (22, 23, 31) that are reduced regulation is implicated in several disease processes, including
in concentration. autoimmune diseases and chronic inflammatory proliferative
At least 5 AP proteins are directly involved in iron trafficking diseases (32). IL-6 signals through its cell surface IL-6–binding
(Figure 1): transferrin, the transport/redox protein ceruloplasmin, protein, IL-6R, coupled to the accessory signaling protein
4S of 7S ROSS

glycoprotein 130; these signals are transduced from the cell to oxygen and oxidant and antioxidant signaling (39), as well as
surface intracellularly through several additional protein factors genetic factors (34, 40). As listed in Table 1, numerous factors
including the protein signal transducer and activator of tran- and physiologic states result in the increased or decreased ex-
scription (STAT) 3 (33). pression of HAMP and concentrations of hepcidin in plasma.
As reviewed by Bode et al. (10), signals from infection, injury, Therefore, hepcidin concentrations are very sensitively regu-
inflammation, or neoplasms induce a response by macrophages lated, and it can be anticipated that iron efflux from cells is
and monocytes and other inflammatory cells that results in the regulated in parallel. As the “master regulator” of iron metab-
release of mediators. These factors then, in liver, influence olism, the hepcidin-ferroportin axis serves to control iron ab-
Kupffer cells and sinusoidal endothelial cells to produce addi- sorption (enterocytes), iron in the extracellular space (via
tional cytokines (IL-1, IL-6, TNF) that are received by receptors sequestration in macrophages), and transplacental iron transport,
on the adjacent hepatocytes and regulate the APR. Examples via regulation of FPN on syncytiotrophoblasts (4, 5, 10, 14).
based on model studies in isolated murine hepatocytes show that
IL-1b can either suppress the induction of protein synthesis by
IL-6, with little to no induction by IL-1b alone as in the case of THE APR AS A MEANS TO DEPRIVE MICROBES OF
g-fibrinogen mRNA expression; or as shown for hepcidin NUTRIENTS
mRNA, IL-1b can strongly synergize with IL-6, whereas neither Excellent reviews (4, 5) have addressed the fundamental
cytokine by itself is a strong inducer [Figure 1B, C in (10)]. competition for iron between the host (human or animal) and
These studies represent the potential and complexity of cytokine infectious agents, many if not most of which require iron for
regulation of the APR. However, further studies in primary growth, and therefore iron availability constitutes a virulence
human hepatocytes, especially those that are representative of factor. In the host-microbe competition for this essential nutrient,
different metabolic and physiologic states, including trimesters microbes have evolved sophisticated strategies to outcompete the
of pregnancy and age (infancy to adult), would be very desirable host, including the production of siderophores with high affinity
for a better understanding of the impact of inflammatory me- for iron. Soares and Wiess (4) comment on host mechanisms that
diators, in addition to IL-1b and IL-6, on the hepatic APR and are cytotoxic to the offending microbes, but also, “However,
AP protein production under a range of conditions. there are also resistance mechanisms..that prevent pathogens
With regard to the differences in response to IL-1b and IL-6 from accessing metabolites and/or nutrients that are essential for
reported by Bode et al. (10), several potential mechanisms were their survival and/or proliferation,” a defense strategy they refer
suggested, including cross-regulation of IL-1b and IL-6 soon to as “nutritional immunity,” which comprises ways that the host
after cell surface signaling, intracellular induction or suppres- attempts to limit iron availability to the infectious bacteria.
sion involving specific protein factors, competition at the level These investigators present the general principle that “Adaptive
of transcription factor binding to DNA elements, and seques- responses supplying Fe to microbes increase, in most cases, their
tration of transcription factors on cryptic or unproductive DNA pathogenicity, while those withholding Fe from microbes limit
sites, any or all of which could affect the transcriptional regu- their virulence” (4).
lation (the main form of regulation) of the production of AP What host responses help in compensation? This question is
proteins (10). To move from bench to bedside, or public health, interesting because the appropriate response depends on whether
these mechanisms, too, will be important to elucidate in cells the pathogen resides intracellularly [examples such as Candida,
that represent various physiologic conditions. Chlamydia, Legionella, Salmonella, and Mycobacterium species
(4)] or extracellularly (examples such as blood-phase malaria).
The issue is important because the location of the pathogen may
HEPCIDIN AS AN AP PROTEIN IN THE RESPONSE TO affect the outcome to host supplementation with iron. With re-
INFLAMMATION gard to extracellular iron and extracellular pathogens, clinical
Liver is the major site of hepcidin synthesis, as indicated by and epidemiologic studies have shown that host iron overload is
higher concentrations of hepcidin antimicrobrial peptide associated with poor clinical outcomes in diseases such as
(HAMP) mRNA in hepatocytes, compared with other organs and AIDS, malaria, and tuberculosis (4) and that dietary iron sup-
cells; however, it is interesting that HAMP mRNA is also de- plementation (assumed to increase extracellular iron initially)
tectable, albeit at lower concentrations, in other tissues and cell can exacerbate overall mortality rate in areas of endemic in-
types and may be synthesized in cells that also express FPN fectious diseases (5). Unbound iron in the host is a source of iron
[reviewed in (34)]. As noted above, HAMP is regulated mainly to extracellular pathogens; moreover, extra- and intracellular
transcriptionally. The hepcidin protein is first translated as an unbound iron can generate toxic free radicals and potentially
84-amino acid preprohormone, cleaved co-translationally to a result in tissue damage. Therefore, counteracting mechanisms to
60-amino acid prohormone, and secreted as a 25-amino acid limit the concentration of unbound iron are extremely important.
hormone. A shortened form, hepcidin-20 (Hep-20), which lacks These include the chaperoning of iron by transferrin in plasma
the first 5 N-terminal amino acids, appears to have antimicrobial [which also targets iron via the interaction of transferrin with the
activity but lacks iron regulatory activity (34, 35). Hepcidin was plasma membrane-associated transferrin receptor (TfR), CD71];
initially called liver-expressed antimicrobial protein (LEAP) 1 lactoferrin, which is present in milk and other secretions (41);
on the basis of its antimicrobial function (36). ferritin as an intracellular chaperone and high-capacity seques-
A variety of factors may contribute to the regulation of HAMP trant of iron; hemoglobin, as the functionally important carrier
expression, mostly shown in vitro, including a suppressive effect of most iron; haptoglobin, as the chaperone of unbound hemo-
of hepatocyte nuclear factor (HNF) 4 (37), induction by factors globin [such as that released from RBCs at sites of injury and
related to endoplasmic reticulum stress (38), and factors related hemolysis (9, 18)]; and hemopexin, an intracellular chaperone
 INFLAMMATION AND IRON HOMEOSTASIS 5S of 7S
TABLE 1
Hepcidin characteristics and regulation1
Characteristics Site of synthesis or action Functions and regulation

Peptide hormone (25-amino acid); Multiple (4); presumably where “Innate nutritional response” factor;
short form, Hep-20 bacteria reside (35) antimicrobial activity (greater for Hep-20?)
“Master regulator” of iron metabolism Binds and assists further degradation of Acts in conjunction with FPN protein to
FPN present on the basolateral limit the efflux/export of iron from
membrane of enterocytes (7, 8); FPN-expressing cells
liver and splenic macrophages;
placental syncytiotrophoblast cells (14)
Synthesis is mainly regulated Liver parenchymal cells; others? Induced by hyperferremia, cytokines (IL-1, IL-6, and IL-22;
at the level of transcription (mRNA detected extrahepatic tissues (34) type I interferons), LPS/toll-like receptor 4 signaling,
intracellular innate inflammatory responses, and
repressed by hypoferremia/iron deficiency, anemia, tissue
hypoxia (increased erythropoietic drive) (13, 34)2
1
FPN, ferroportin; Hep-20, hepcidin-20; mRNA, messenger RNA.
2
Underlined text indicates factors related to inflammation.

for free heme, which interacts with the enzyme heme oxygenase 1 damaged RBCs, can induce phagocytosis and the release of
(HO-1), to catabolize free heme (17). It is also relevant that heme, which may scavenge nitrous oxide and cause local
transferrin is normally only partially saturated with iron, providing a vasoconstriction. Released oxidized heme, as a ligand for
reserve of “iron binding capacity” to take up free iron when it is in G-protein-coupled receptors on polymorphonuclear leukocytes,
excess. may stimulate the release of reactive oxygen species and cause
The ability of macrophages to take up and store iron is well more damage; and released oxidized heme may serve as a ligand
known (9), and Kupffer cells have an especially high capacity for for Toll-like receptors on endothelial cells, causing endothelial
the storage of excess iron (42). Schematically (Figure 2), inflammation. Scavenging of heme iron and oxidized heme are
macrophage iron metabolism should be regulated differentially important for reducing their presence in the extracellular fluid,
in response to the presence of extracellular pathogens (Figure and HO-1 is an important intracellular control mechanism for the
2A) and intracellular pathogens (Figure 2B), the common degradation of free heme (43). Moreover, one of its reaction
products, carbon monoxide, is cytoprotective (43, 44).
“theme” being to reduce the co-compartmentalization of the
pathogen or pathogens and available iron. Several potential
mechanisms are listed in Figure 2. PREGNANCY AND INFANCY
The microvasculature is also sensitive to iron status and the Information on the mechanisms of the regulation of iron
products of RBC damage [reviewed in (4)]. Free heme is a danger transport and metabolism, as affected by inflammation, in
signal; oxidized heme released from infected RBCs has multiple pregnancy and in newborns is extremely limited. With respect to
effects on tissue microvasculature and tissue damage, including CRP concentrations as a general indicator of inflammation,

FIGURE 2 Schematic of differential adaptive responses to segregate iron from microbes in the situation with extracellular infectious agents in which
sequestration of iron intracellularly generally favors the host’s response (A) and with intracellular infectious agents in which removal of iron from the cell
generally favors the host’s response to infection (B). (See references 4 and 5 for additional information). FPN, ferroportin.
6S of 7S ROSS

systemic CRP concentrations in pregnancy have been found to needed. Because hepcidin is now well established as a major
be within the range that is normal for healthy, nonpregnant regulator, additional studies on the meaning of HAMP expression
individuals (45), or categorized as “normal/insignificant” in extrahepatic tissues would also be timely.
(,1 mg/dL) (24). Yet, whether more local tissue differences A key question is to what extent small differences in in-
exist is not well known. Studies of implantation have shown flammatory status (and how these should be assessed) affect
that a controlled, local immune response, characterized by the hepcidin concentrations and to what extent these differences
presence of IL-6, IL-8, TNF, and T-helper 1 cells, is essential for actually result in tangible changes in iron transport, intracellular
implantation, which, if blocked, results in implantation fail- iron storage and metabolism, and functional outcomes. Over-
ure (46). Similarly, parturition requires a local uterine or sys- laying all of this is the effect of infection, the differences in
temic inflammatory response (47). Thus, understanding the response to extracellular and intracellular microbes, and their
impact of “inflammation” on iron status in pregnancy will re- impact on health and survival.
quire studies that specifically consider local and systemic in-
The author was solely responsible for the manuscript. The author had no
flammation and that integrate knowledge of iron-regulatory conflict of interest related to the study.
pathways with acceptable biomarkers of inflammation. Hepcidin
concentrations decrease and become very low in the course of
pregnancy but are higher in pregnancy with inflammation (14).
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