Genomic Organization and Chromosomal Localization of the Human CD163 (M130) Gene: A Member of the Scavenger Receptor Cysteine-Rich Superfamily

doi:10.1006/bbrc.1999.0866

Biochemical and Biophysical Research Communications

Volume 260, Issue 2, 5 July 1999, Pages 466-474

https://doi.org/10.1006/bbrc.1999.0866 Get rights and content

Abstract

The human protein CD163 (M130) is a member of the scavenger receptor cysteine-rich (SRCR) superfamily, which is exclusively expressed by monocytes and macrophages. Here, we investigated the genomic organization and the chromosomal localization of the human CD163 gene. The CD163 gene is composed of 17 exons and 16 introns and spans over 35 kb. Each of its nine SRCR domains is encoded by a separate exon, which is similar to other members of the group B SRCR subfamily. Two cytoplasmic variants of CD163 arise from alternative splicing of intron 15, while a truncated and an extracellular variant results from alternative splicing of intron 5 or intron 7, respectively. Using fluorescence in situ hybridization we mapped this gene to the human chromosome 12p13. The transcription initiation sites of the CD163 gene were determined and the 5′-flanking region was sequenced. The nucleotide analysis revealed several putative binding sites for transcription factors, which have been shown to play an important role in myeloid specific gene expression. In addition, we identified a L1 element located 1.4 kb upstream of the major transcription initiation site.

References (45)

D. Resnick et al.
Trends. Biochem. Sci.
(1994)
O. Elomaa et al.
Cell
(1995)
K. Koths et al.
J. Biol. Chem.
(1993)
G. Goldberger et al.
J. Biol. Chem.
(1987)
H. Saito et al.
J. Biol. Chem.
(1997)
J.A. Gebe et al.
J. Biol. Chem.
(1997)
W.E. Mayer et al.
Gene
(1995)
X.J. Li et al.
J. Biol. Chem.
(1995)
M. Emi et al.
J. Biol. Chem.
(1993)
R.P. Aftring et al.
J. Lipid Res.
(1995)

T.J. Vyse et al.

Genomics

(1994)

R. Gallagher et al.

Blood

(1979)

H. Kobayashi et al.

Blood

(1994)

L.T. Smith et al.

Blood

(1996)

D.G. Tenen et al.

Blood

(1997)

T.G. Fanning et al.

Biochim. Biophys. Acta

(1987)

A.D. Gruber et al.

Genomics

(1998)

Z.K. Indik et al.

Blood

(1994)

T. Kodama et al.

Nature

(1990)

Y. Kitamoto et al.

Biochemistry

(1995)

L.J. Dangott et al.

Proc. Natl. Acad. Sci. USA

(1989)

S.K. Law et al.

Eur. J. Immunol.

(1993)

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CD163 expressed on cell surface of porcine alveolar macrophages (PAMs) serves as a cellular entry receptor for porcine reproductive and respiratory syndrome virus (PRRSV). The extracellular portion of CD163 contains nine scavenger receptor cysteine-rich (SRCR) and two proline-serine-threonine (PST) domains. Genomic editing of pigs to remove the entire CD163 or just the SRCR5 domain confers resistance to infection with both PRRSV-1 and PRRSV-2 viruses. By performing a mutational analysis of CD163, previous in vitro infection experiments showed resistance to PRRSV infection following deletion of exon 13 which encodes the first 12 amino acids of the 16 amino acid PSTII domain. These findings predicted that removal of exon 13 can be used as a strategy to produce gene-edited pigs fully resistant to PRRSV infection. In this study, to determine whether the deletion of exon 13 is sufficient to confer resistance of pigs to PRRSV infection, we produced pigs possessing a defined CD163 exon 13 deletion (ΔExon13 pigs) and evaluated their susceptibility to viral infection. Wild type (WT) and CD163 modified pigs, placed in the same room, were infected with PRRSV-2. The modified pigs remained PCR and serologically negative for PRRSV throughout the study; whereas the WT pigs supported PRRSV infection and showed PRRSV related pathology. Importantly, our data also suggested that removal of exon 13 did not affect the main physiological function associated with CD163 in vivo. These results demonstrate that a modification of CD163 through a precise deletion of exon 13 provides a strategy for protection against PRRSV infection.
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Macrophage activation and hypercytokinemia are notable presentations in certain viral infections leading to severe disease and poor prognosis. Viral infections can cause macrophage polarization into the pro-inflammatory M1 or anti-inflammatory M2 phenotype. Activated M1 macrophages usually restrict viral replication whereas activated M2 macrophages suppress inflammation and promote tissue repair. In response to inflammatory stimuli, macrophages polarize to the M2 phenotype expressing hemoglobin scavenger CD163 surface receptor. The CD163 receptor is shed as the soluble form, sCD163, into plasma or tissue fluids. sCD163 causes detoxification of pro-oxidative hemoglobin which produces anti-inflammatory metabolites that promote the resolution of inflammation. Hence, increased CD163 expression in tissues and elevated circulatory levels of sCD163 have been associated with acute and chronic inflammatory diseases. CD163 and other macrophage activation markers have been commonly included in the investigation of disease pathogenesis and progression. This review provides an overview of the involvement of CD163 in viral diseases. The clinical utility of CD163 in viral disease diagnosis, progression, prognosis and treatment evaluation is discussed.
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Porcine CD163, which serves as a cellular entry receptor for PRRSV, is a type I transmembrane protein that belongs to the class B of the scavenger receptor cysteine-rich (SRCR) superfamily (SRCR-SF) (Fabriek et al., 2005, 2007; Law et al., 1993; Ritter et al., 1999; Su et al., 2021). CD163 is an endocytic receptor expressed exclusively in cells of the monocyte-macrophage lineage (Law et al., 1993; Ritter et al., 1999). CD163-positive macrophages, specially porcine alveolar macrophages (PAMs), are the PRRSV main target cells in vivo (Duan et al., 1997).
CD163, a receptor for porcine reproductive and respiratory syndrome virus (PRRSV), possesses nine scavenger receptor cysteine-rich (SRCR) and two proline-serine-threonine (PST) domains. To identify CD163 regions involved in PRRSV infection, CD163 mutants were generated. Infection experiments showed resistance to infection following deletion of the SRCR4/5 interdomain or the Exon 13 that encodes a portion of PSTII. The mutation of a pentapeptide domain in SRCR5 and SRCR7 also conferred resistance. Mutant CD163 proteins that resisted infection retained the ability to interact with GP2, GP3, GP4 and GP5 viral glycoproteins. The contribution of multiple domains to infection but not to the binding of viral glycoproteins suggests that the envelope proteins may form multiple interactions with CD163, or that receptor regions important for infection have other cellular binding partners required for PRRSV infection. Finally, we mapped the localization the anti-CD163 2A10 antibody epitope.
Post-transcriptional regulation through alternative splicing in the lungs of Tibetan pigs under hypoxia
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CD163 generates all five AS types, and several other genes, including SLC25A29, SNAPC1, OBSL1, OBSCN, MKI67, IL1A and NDRG2, have four types of AS events. Our analysis indicates that AS plays an indispensable role in producing different proteins and transcripts to affect the lungs in the regulation of gene expression during hypoxia (Ritter et al., 1999). Hypoxia can regulate the AS of hypoxia-induced genes and genes whose transcription is not changed by hypoxia (Sena et al., 2014).
In multicellular organisms, alternative splicing (AS) is central to the regulation of multiple biological processes. To further elucidate the adaptive strategy of AS in the lungs of Tibetan pigs in response to hypoxia, we identified and analyzed five basic AS types and 59,930 AS events in 18,179 genes. We found that approximately 65.10% of the total expressed genes underwent AS in the lungs of Tibetan pigs at a high altitude (TH). The frequencies of AS events were similar among the different groups (5.06–5.30 events in each gene on average). Skipped exons (SEs) were the predominant type of AS event, followed by mutually exclusive exons (MXEs), alternative 3′ splice sites (A3SSs) and alternative 5′ splice sites (A5SSs). Retained introns (RIs), the remaining type of AS event, showed lower frequencies. Further comparison analysis of differentially expressed genes (DEGs) and differentially spliced genes (DSGs) identified 2,209 differential splicing events in the above 18,000 expressed genes, including 918 increased and 1,291 decreased splicing events between the TH and Tibetan pigs at a low altitude (TL) groups. We identified 227 hypoxia-related genes involved in lung development that were differentially regulated through AS. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis clearly identified many DEGs and DSGs at high or low altitude. Seven pathways in the top 20 enriched KEGG terms overlapped for the DEGs and DSGs, including the chemokine signaling pathway, B cell receptor signaling pathway, and cytokine–cytokine receptor interaction, which exert many immunoregulatory and inflammatory actions critical to the lung under hypoxia. Twelve pathways overlapped in hypoxic DEGs and DSGs and included antigen processing, presentation and biosynthesis. GO analysis of the DEGs and DSGs among the four groups showed that numerous GO terms were enriched in the biological category, and the proportion of genes with downregulated expression was greater among 227 hypoxic genes than that of all genes. The results suggest that AS plays an essential role in the regulation of gene expression during hypoxia and that numerous genes involved in lung development are differentially regulated through AS.
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CD163 is a macrophage scavenger receptor with anti-inflammatory and pro-inflammatory functions. Here, we report that alveolar macrophages (AMΦs) from asthmatic subjects had reduced cell-surface expression of CD163, which suggested that CD163 might modulate the pathogenesis of asthma. Consistent with this, house dust mite (HDM)-challenged Cd163^−/− mice displayed increases in airway eosinophils and mucous cell metaplasia (MCM). The increased airway eosinophils and MCM in HDM-challenged Cd163^−/− mice were mediated by augmented CCL24 production and could be reversed by administration of a neutralizing anti-CCL24 antibody. A proteomic analysis identified the calcium-dependent binding of CD163 to Dermatophagoides pteronyssinus peptidase 1 (Der p1). Der p1-challenged Cd163^−/− mice had the same phenotype as HDM-challenged Cd163^−/− mice with increases in airway eosinophils, MCM and CCL24 production, while Der p1 induced CCL24 secretion by bone marrow-derived macrophages (BMMΦs) from Cd163^−/− mice, but not BMMΦs from wild-type (WT) mice. Finally, airway eosinophils and bronchoalveolar lavage fluid CCL24 levels were increased in Der p1-challenged WT mice that received adoptively transferred AMΦ's from Cd163^−/− mice. Thus, we have identified CD163 as a macrophage receptor that binds Der p1. Furthermore, we have shown that HDM-challenged Cd163^−/− mice have increased eosinophilic airway inflammation and MCM that are mediated by a CCL24-dependent mechanism.
Expression of soluble sCD163 in serum of psoriatic patients is modulated by Goeckerman therapy
2013, Allergologia et Immunopathologia
Citation Excerpt :
CD163 is the monocyte/macrophage receptor for haptoglobin–haemoglobin (Hp–Hb) complexes.6,7 It is a member of the scavenger receptor cysteine-rich (SRCR) superfamily8,9; specifically, it belongs to Group B superfamily.7,10,11 Many of the SRCR-proteins have been shown to be directly involved in the development of the immune system and in the regulation of the immune response.
CD163 is the monocyte/macrophage receptor for haptoglobin–haemoglobin complexes. The aim of this study was to assess the kinetics in the expression of CD163 on monocytes and the concentration of soluble sCD163 in serum of psoriatic patients in order to examine the effect of Goeckerman therapy.
sCD163 was measured in 71 patients before and after therapy, and in 57 healthy donors. A subgroup of 40 patients and 25 controls was used to assess the expression of membrane CD163. sCD163 was evaluated by ELISA. Flow cytometry method was used to determine the expression of membrane CD163 on monocytes, expressed as mean fluorescence index (MFI).
Before therapy, the serum level of sCD163 was significantly higher in our patients than in controls (P = 0.0154). However, we observed a profound decrease in sCD163 in our patients after therapy (P = 0.0037). Similar to sCD163, pre-treatment expression of CD163 on monocytes was significantly more enhanced in patients than that in controls (P = 0.0078). There was a trend towards down-regulation of the expression after therapy, nonetheless, the change was not statistically significant compared to the values before therapy (P = 0.8666). This was also confirmed by comparison with controls which displayed lower expression of CD163 than patients after therapy (P = 0.0019). The disease activity, expressed as PASI score, was significantly decreased in our patients by GT (P = 0.0001).
While sCD163 level in psoriatic patients was diminished after GT therapy, CD163 expression on monocytes was altered only to a minor extent.

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^☆: Sequence data from this article have been submitted to the EMBL/GenBank Data Libraries under Accession Nos. Y18388 to Y18403 (exons 1 to 16), AJ133107 (exon 17), and AJ224687 (5′-flanking region).

^☆☆: Abbreviations used: DAPI, 4′,6-diamidino-2-phenylindole-dihydrochloride; FISH, fluorescence in situ hybridization; M-CSF, macrophage colony-stimulating factor; RACE, rapid amplification of cDNA ends; SRCR, scavenger receptor cysteine-rich; UTR, untranslated region

²: To whom correspondence should be addressed at Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauß-Allee 11, D-93042 Regensburg, Germany. Fax: (49)-941-944-6202. E-mail: [email protected].

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Regular ArticleGenomic Organization and Chromosomal Localization of the Human CD163 (M130) Gene: A Member of the Scavenger Receptor Cysteine-Rich Superfamily☆,☆☆

Abstract

Trends. Biochem. Sci.

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Gene

J. Biol. Chem.

J. Biol. Chem.

J. Lipid Res.

Genomics

Blood

Blood

Blood

Blood

Biochim. Biophys. Acta

Genomics

Blood

Nature

Biochemistry

Proc. Natl. Acad. Sci. USA

Eur. J. Immunol.

Regular Article
Genomic Organization and Chromosomal Localization of the Human CD163 (M130) Gene: A Member of the Scavenger Receptor Cysteine-Rich Superfamily☆,☆☆