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Splenic Macrophage Subsets and Their Function during Blood-Borne Infections.

Borges da Silva H, Fonseca R, Pereira RM, Cassado Ados A, Álvarez JM, D'Império Lima MR - Front Immunol (2015)

Bottom Line: Marginal metallophilic macrophages (MMMΦs) and marginal zone macrophages (MZMΦs) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria.Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity.Indeed, MMMΦs and MZMΦs are considered important bridges between innate and adaptive immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo , São Paulo , Brazil.

ABSTRACT
The spleen is one of the major immunological sites for maintaining blood homeostasis. Previous studies showed that heterogeneous splenic macrophage populations contribute in complimentary ways to control blood-borne infections and induce effective immune responses. Marginal metallophilic macrophages (MMMΦs) and marginal zone macrophages (MZMΦs) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria. Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity. Indeed, MMMΦs and MZMΦs are considered important bridges between innate and adaptive immunity. Although red pulp macrophages (RpMΦs) are mainly considered scavengers for senescent erythrocytes, several data indicate a role for RpMΦs in control of infections such as blood-stage malaria as well as in the induction of innate and adaptive immunity. Here, we review current data on how different macrophage subsets recognize and help eliminate blood-borne pathogens, and, in turn, how the inflammatory microenvironment in different phases of infection (acute, chronic, and after pathogen clearance) influences macrophage function and survival.

No MeSH data available.


Related in: MedlinePlus

RpMΦ biology during homeostasis and infection. This figure summarizes the different roles of RpMΦs in maintenance of host homeostasis and in the control of different infections. In the absence of infection (left), RpMΦs play important roles in the uptake of apoptotic cells, oxidized LDL (oxLDL), or senescent RBCs (sRBCs) from the circulations, through interaction with receptors such as SIRPα, CD36, CR3, or FcRs. CD47 expression on RBCs is an inhibitory signal for phagocytosis mediated by SIRPα, but sRBCs expressing a modified isoform of this molecule (altCD47) are phagocytized by RpMΦs. CD36 binds to phosphatidylserine (PS) and, alternatively, to oxLDL. RpMΦs are also important for iron homeostasis, and conversely, iron homeostasis seems to control RpMΦ development, through the action of free heme on Spi-C transcriptional factor. In these situations, RpMΦs have the ability of self-renewal by proliferation. Beyond the task of maintaining blood homeostasis, RpMΦs contribute to control blood-borne infections such as malaria (center) or bacterial infections (right) lead to changes in RpMΦ function. Plasmodium-infected RBCs (iRBCs) are recognized through the same receptors that recognize sRBCs, such as SIRPα, CR3, FcRs, or CD36, inferring a role for RpMΦs in parasite clearance. However, the adherence of iRBCs to microvascular endothelium through CD36 prevents iRBC clearance inside the spleen. Interestingly, P. yoelii parasites preferentially infect young RBCs expressing high levels of CD47 and, in consequence, escape from splenic clearance. RpMΦs also present with other receptors such as CLRs and PPRs, which in conjunct with FcγRIII contribute to recognition and elimination of bacteria from circulation. RpMΦs can recognize the capsular polysaccharide glucuronoxylomannan (GXM) from Cryptococcus neoformans and subsequently phagocytize the bacteria. The ability of RpMΦ renewal during infections, however, is poorly understood, and substitution of dead RpMΦs for monocyte-derived RpMΦs is presumable.
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Figure 2: RpMΦ biology during homeostasis and infection. This figure summarizes the different roles of RpMΦs in maintenance of host homeostasis and in the control of different infections. In the absence of infection (left), RpMΦs play important roles in the uptake of apoptotic cells, oxidized LDL (oxLDL), or senescent RBCs (sRBCs) from the circulations, through interaction with receptors such as SIRPα, CD36, CR3, or FcRs. CD47 expression on RBCs is an inhibitory signal for phagocytosis mediated by SIRPα, but sRBCs expressing a modified isoform of this molecule (altCD47) are phagocytized by RpMΦs. CD36 binds to phosphatidylserine (PS) and, alternatively, to oxLDL. RpMΦs are also important for iron homeostasis, and conversely, iron homeostasis seems to control RpMΦ development, through the action of free heme on Spi-C transcriptional factor. In these situations, RpMΦs have the ability of self-renewal by proliferation. Beyond the task of maintaining blood homeostasis, RpMΦs contribute to control blood-borne infections such as malaria (center) or bacterial infections (right) lead to changes in RpMΦ function. Plasmodium-infected RBCs (iRBCs) are recognized through the same receptors that recognize sRBCs, such as SIRPα, CR3, FcRs, or CD36, inferring a role for RpMΦs in parasite clearance. However, the adherence of iRBCs to microvascular endothelium through CD36 prevents iRBC clearance inside the spleen. Interestingly, P. yoelii parasites preferentially infect young RBCs expressing high levels of CD47 and, in consequence, escape from splenic clearance. RpMΦs also present with other receptors such as CLRs and PPRs, which in conjunct with FcγRIII contribute to recognition and elimination of bacteria from circulation. RpMΦs can recognize the capsular polysaccharide glucuronoxylomannan (GXM) from Cryptococcus neoformans and subsequently phagocytize the bacteria. The ability of RpMΦ renewal during infections, however, is poorly understood, and substitution of dead RpMΦs for monocyte-derived RpMΦs is presumable.

Mentions: Apart from being phagocytized by splenic MΦs, Plasmodium-iRBCs are also destroyed intravascularly as a consequence of plasma membrane damage upon release of free merozoites. Hemozoin, a disposal product formed from hemoglobin digestion by parasites, is released from lysed iRBCs. Furthermore, a massive destruction of non-infected RBCs occurs during blood-stage malaria, leading to increased hemoglobin levels in circulation [reviewed in Ref. (47)]. Another example of hemolysis induced by infections is observed in septicemia caused by Escherichia coli, which produces exotoxin α-hemolysin (Hlyα) (48). Evidencing RpMΦs crucial role in neutralizing toxic effects of hemoglobin, these MΦs have high levels of intracellular heme due to RBC phagocytosis (2) and of free hemoglobin through the scavenger receptor CD163 (49). The enzyme heme-oxygenase 1 (HO-1) plays an important role in degrading free heme, which in excess causes toxicity to MΦs (50). Importantly, RpMΦs are able to control pathogen burden through control of iron availability. For example, RpMΦs express the natural resistance associated macrophage protein-1 (NRAMP1) that is associated with protection against intraphagosomal pathogens, such as Mycobacterium bovis BCG, Leishmania donovani, or S. typhimurium. This molecule is a pH-dependent metal transporter localized in phagosomal compartments, which reduces intraphagosomal iron levels derived from RBC phagocytosis (51). NRAMP1 synthesis is upregulated in IFN-γ-activated MΦs (52), a condition likely to occur during acute blood-borne infections. RpMΦs also limit pathogen iron uptake through TLR-mediated release of lipocalin-2, which can form complexes with pathogen-secreted siderophores – molecules that help the collection of iron available for pathogens (53). RpMΦs involvement in controlling excessive immune responses is suggested by studies on autoimmune syndromes, while a similar participation in infectious diseases remains to be established. For instance, RpMΦs constitutively express peroxisome proliferator-activated receptor-γ (PPAR-γ), which might be important to curb excessive immune responses to pathogens, in a similar manner to PPAR-γ expressed on lung MΦs upon S. pneumoniae infection (54). RPMΦs can also prevent autoimmunity by producing anti-inflammatory cytokines such as TGF-β and IL-10 and by inducing generation of regulatory T (Treg) cells (55). Of note, there are many T cells scattered in Rp (55), and this population participates in acute immune responses to infections, such as blood-stage malaria (39). We present an illustrated scheme of the different roles of RpMΦs in homeostasis and disease in Figure 2.


Splenic Macrophage Subsets and Their Function during Blood-Borne Infections.

Borges da Silva H, Fonseca R, Pereira RM, Cassado Ados A, Álvarez JM, D'Império Lima MR - Front Immunol (2015)

RpMΦ biology during homeostasis and infection. This figure summarizes the different roles of RpMΦs in maintenance of host homeostasis and in the control of different infections. In the absence of infection (left), RpMΦs play important roles in the uptake of apoptotic cells, oxidized LDL (oxLDL), or senescent RBCs (sRBCs) from the circulations, through interaction with receptors such as SIRPα, CD36, CR3, or FcRs. CD47 expression on RBCs is an inhibitory signal for phagocytosis mediated by SIRPα, but sRBCs expressing a modified isoform of this molecule (altCD47) are phagocytized by RpMΦs. CD36 binds to phosphatidylserine (PS) and, alternatively, to oxLDL. RpMΦs are also important for iron homeostasis, and conversely, iron homeostasis seems to control RpMΦ development, through the action of free heme on Spi-C transcriptional factor. In these situations, RpMΦs have the ability of self-renewal by proliferation. Beyond the task of maintaining blood homeostasis, RpMΦs contribute to control blood-borne infections such as malaria (center) or bacterial infections (right) lead to changes in RpMΦ function. Plasmodium-infected RBCs (iRBCs) are recognized through the same receptors that recognize sRBCs, such as SIRPα, CR3, FcRs, or CD36, inferring a role for RpMΦs in parasite clearance. However, the adherence of iRBCs to microvascular endothelium through CD36 prevents iRBC clearance inside the spleen. Interestingly, P. yoelii parasites preferentially infect young RBCs expressing high levels of CD47 and, in consequence, escape from splenic clearance. RpMΦs also present with other receptors such as CLRs and PPRs, which in conjunct with FcγRIII contribute to recognition and elimination of bacteria from circulation. RpMΦs can recognize the capsular polysaccharide glucuronoxylomannan (GXM) from Cryptococcus neoformans and subsequently phagocytize the bacteria. The ability of RpMΦ renewal during infections, however, is poorly understood, and substitution of dead RpMΦs for monocyte-derived RpMΦs is presumable.
© Copyright Policy
Related In: Results  -  Collection

License
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Figure 2: RpMΦ biology during homeostasis and infection. This figure summarizes the different roles of RpMΦs in maintenance of host homeostasis and in the control of different infections. In the absence of infection (left), RpMΦs play important roles in the uptake of apoptotic cells, oxidized LDL (oxLDL), or senescent RBCs (sRBCs) from the circulations, through interaction with receptors such as SIRPα, CD36, CR3, or FcRs. CD47 expression on RBCs is an inhibitory signal for phagocytosis mediated by SIRPα, but sRBCs expressing a modified isoform of this molecule (altCD47) are phagocytized by RpMΦs. CD36 binds to phosphatidylserine (PS) and, alternatively, to oxLDL. RpMΦs are also important for iron homeostasis, and conversely, iron homeostasis seems to control RpMΦ development, through the action of free heme on Spi-C transcriptional factor. In these situations, RpMΦs have the ability of self-renewal by proliferation. Beyond the task of maintaining blood homeostasis, RpMΦs contribute to control blood-borne infections such as malaria (center) or bacterial infections (right) lead to changes in RpMΦ function. Plasmodium-infected RBCs (iRBCs) are recognized through the same receptors that recognize sRBCs, such as SIRPα, CR3, FcRs, or CD36, inferring a role for RpMΦs in parasite clearance. However, the adherence of iRBCs to microvascular endothelium through CD36 prevents iRBC clearance inside the spleen. Interestingly, P. yoelii parasites preferentially infect young RBCs expressing high levels of CD47 and, in consequence, escape from splenic clearance. RpMΦs also present with other receptors such as CLRs and PPRs, which in conjunct with FcγRIII contribute to recognition and elimination of bacteria from circulation. RpMΦs can recognize the capsular polysaccharide glucuronoxylomannan (GXM) from Cryptococcus neoformans and subsequently phagocytize the bacteria. The ability of RpMΦ renewal during infections, however, is poorly understood, and substitution of dead RpMΦs for monocyte-derived RpMΦs is presumable.
Mentions: Apart from being phagocytized by splenic MΦs, Plasmodium-iRBCs are also destroyed intravascularly as a consequence of plasma membrane damage upon release of free merozoites. Hemozoin, a disposal product formed from hemoglobin digestion by parasites, is released from lysed iRBCs. Furthermore, a massive destruction of non-infected RBCs occurs during blood-stage malaria, leading to increased hemoglobin levels in circulation [reviewed in Ref. (47)]. Another example of hemolysis induced by infections is observed in septicemia caused by Escherichia coli, which produces exotoxin α-hemolysin (Hlyα) (48). Evidencing RpMΦs crucial role in neutralizing toxic effects of hemoglobin, these MΦs have high levels of intracellular heme due to RBC phagocytosis (2) and of free hemoglobin through the scavenger receptor CD163 (49). The enzyme heme-oxygenase 1 (HO-1) plays an important role in degrading free heme, which in excess causes toxicity to MΦs (50). Importantly, RpMΦs are able to control pathogen burden through control of iron availability. For example, RpMΦs express the natural resistance associated macrophage protein-1 (NRAMP1) that is associated with protection against intraphagosomal pathogens, such as Mycobacterium bovis BCG, Leishmania donovani, or S. typhimurium. This molecule is a pH-dependent metal transporter localized in phagosomal compartments, which reduces intraphagosomal iron levels derived from RBC phagocytosis (51). NRAMP1 synthesis is upregulated in IFN-γ-activated MΦs (52), a condition likely to occur during acute blood-borne infections. RpMΦs also limit pathogen iron uptake through TLR-mediated release of lipocalin-2, which can form complexes with pathogen-secreted siderophores – molecules that help the collection of iron available for pathogens (53). RpMΦs involvement in controlling excessive immune responses is suggested by studies on autoimmune syndromes, while a similar participation in infectious diseases remains to be established. For instance, RpMΦs constitutively express peroxisome proliferator-activated receptor-γ (PPAR-γ), which might be important to curb excessive immune responses to pathogens, in a similar manner to PPAR-γ expressed on lung MΦs upon S. pneumoniae infection (54). RPMΦs can also prevent autoimmunity by producing anti-inflammatory cytokines such as TGF-β and IL-10 and by inducing generation of regulatory T (Treg) cells (55). Of note, there are many T cells scattered in Rp (55), and this population participates in acute immune responses to infections, such as blood-stage malaria (39). We present an illustrated scheme of the different roles of RpMΦs in homeostasis and disease in Figure 2.

Bottom Line: Marginal metallophilic macrophages (MMMΦs) and marginal zone macrophages (MZMΦs) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria.Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity.Indeed, MMMΦs and MZMΦs are considered important bridges between innate and adaptive immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Instituto de Ciências Biomédicas, Universidade de São Paulo , São Paulo , Brazil.

ABSTRACT
The spleen is one of the major immunological sites for maintaining blood homeostasis. Previous studies showed that heterogeneous splenic macrophage populations contribute in complimentary ways to control blood-borne infections and induce effective immune responses. Marginal metallophilic macrophages (MMMΦs) and marginal zone macrophages (MZMΦs) are cells with great ability to internalize blood-borne pathogens such as virus or bacteria. Their localization adjacent to T- and B-cell-rich splenic areas favors the rapid contact between these macrophages and cells from adaptive immunity. Indeed, MMMΦs and MZMΦs are considered important bridges between innate and adaptive immunity. Although red pulp macrophages (RpMΦs) are mainly considered scavengers for senescent erythrocytes, several data indicate a role for RpMΦs in control of infections such as blood-stage malaria as well as in the induction of innate and adaptive immunity. Here, we review current data on how different macrophage subsets recognize and help eliminate blood-borne pathogens, and, in turn, how the inflammatory microenvironment in different phases of infection (acute, chronic, and after pathogen clearance) influences macrophage function and survival.

No MeSH data available.


Related in: MedlinePlus