Anti-inflammatory activity of CD44 antibodies in murine immune thrombocytopenia is mediated by Fcγ receptor inhibition

Norris, Peter Alan Albert; Kaur, Gurleen; Khan, Ramsha; Zhu, Guangheng; Ni, Heyu; Lazarus, Alan H.

doi:10.1182/blood.2020009497

Cited by 9 publications

(6 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, these combined effects of heightened FcγR-mediated platelet destruction with increased inflammatory signaling in Adap −/− macrophages aggravate the development of thrombocytopenia. In supporting this notion, a recent study suggested that an anti-inflammatory antibody, anti-CD44, ameliorates ITP by inhibiting macrophage FcγR-mediated phagocytosis of platelets after its Fc fragment blocking FcγR IgG binding site (the Kurlander phenomenon) [ 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia

Xiong

Cui

et al. 2022

Cell Mol Immunol

View full text Add to dashboard Cite

Heightened platelet phagocytosis by macrophages accompanied by an increase in IFN-γ play key roles in the etiology of immune thrombocytopenia (ITP); however, it remains elusive how macrophage-mediated platelet clearance is regulated in ITP. Here, we report that adhesion and degranulation-protein adaptor protein (ADAP) restrains platelet phagocytosis by macrophages in ITP via modulation of signal transducer and activator of transcription 1 (STAT1)-FcγR signaling. We show that ITP was associated with the underexpression of ADAP in splenic macrophages. Furthermore, macrophages from Adap −/− mice exhibited elevated platelet phagocytosis and upregulated proinflammatory signaling, and thrombocytopenia in Adap −/− mice was mitigated by the depletion of macrophages. Mechanistically, ADAP interacted and competed with STAT1 binding to importin α5. ADAP deficiency potentiated STAT1 nuclear entry, leading to a selective enhancement of FcγRI/IV transcription in macrophages. Moreover, pharmacological inhibition of STAT1 or disruption of the STAT1-importin α5 interaction relieved thrombocytopenia in Adap −/− mice. Thus, our findings not only reveal a critical role for ADAP as an intracellular immune checkpoint for shaping macrophage phagocytosis in ITP but also identify the ADAP-STAT1-importin α5 module as a promising therapeutic target in the treatment of ITP.

show abstract

Section: Discussionmentioning

confidence: 99%

ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia

Xiong

Cui

et al. 2022

Cell Mol Immunol

View full text Add to dashboard Cite

show abstract

“…However, according to ENSEMBL, the lead SNP rs149514849 is located on the binding site of a transcription factor, and has been associated with variations of the expression of CD44 in macrophages. CD44, a pleiotropic glycoprotein involved in cell-cell interactions, cell adhesion and migration, has a role in the phagocytic process of macrophages [57, 58]. Additionally, the lead SNP rs76559378 at 13q13 is in strong LD ( r 2 = 0·897) with the exonic KL SNP rs201936594 (same GWAS, p = 9·74 x 10 -7 ) which displays a CADD score of 13·94, suggesting a likely deleterious effect.…”

Section: Resultsmentioning

confidence: 99%

Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

Henry

Volle

Akpovi³

et al. 2022

Preprint

View full text Add to dashboard Cite

In malaria-endemic areas, subjects from specific groups like Fulani have a peculiar protection against malaria, with high levels of IgM but also frequent anemia and splenomegaly. The mechanisms underlying this phenotype remain elusive. In Benin, West Africa, we measured the deformability of circulating erythrocytes in genetically distinct groups (including Fulani) living in sympatry, using ektacytometry and microsphiltration, a mimic of how the spleen clears rigid erythrocytes. Compared to non-Fulani, Fulani displayed a higher deformability of circulating erythrocytes, pointing to an enhanced clearance of rigid erythrocytes by the spleen. This phenotype was observed in individuals displaying markers of Plasmodium falciparum infection. The heritability of this new trait was high, with a strong multigenic component. Five of the top 10 genes selected by a population structure-adjusted GWAS, expressed in the spleen, are potentially involved in splenic clearance of erythrocytes (CHERP, MB, PALLD, SPARC, PDE10A), through control of vascular tone, collagen synthesis and macrophage activity. In specific ethnic groups, genetically-controlled processes likely enhance the innate retention of infected and uninfected erythrocytes in the spleen, explaining splenomegaly, anemia, cryptic intrasplenic parasite loads, hyper-IgM, and partial protection against malaria. Beyond malaria-related phenotypes, inherited splenic hyper-filtration of erythrocytes may impact the pathogenesis of other hematologic diseases.Research in contextEvidence before this studyThe genetic background of individuals influences their susceptibility to infectious diseases. Specific human groups, like the Fulani in Africa, react to malaria parasites (named Plasmodium) in a specific way. Upon infection, Fulani develop a grossly enlarged spleen, and high levels of anti-Plasmodium antibodies in their blood. They also carry smaller numbers of parasites in their blood, and thus are considered partially protected against malaria. The mechanisms underlying this natural protection, different from other natural protective mechanisms such as the sickle cell trait, are not well understood.Malaria impairs the deformability of red blood cells and the spleen is a key organ to controlling red blood cell quality. We have recently demonstrated that red blood cells containing live malaria parasites accumulate intensely in the spleen of subjects with long term exposure to these parasites. Enhanced retention of infected and uninfected red blood cells in the spleen would explain why the spleen is larger and why lower numbers of parasites are left in circulation. We thus explored whether the retention of infected and uninfected red blood cells could explain why Fulani are partially protected against malaria. Because it is unethical to perform spleen puncture or biopsies for research purposes, our explorations were indirect by carefully analyzing the properties of circulating red blood cells in a large number of subjects and by assessing whether observations could be explained by their genetic make-up.Added value of this studyIn more than 500 subjects, we confirmed the high frequency of large spleens in Fulani and, through 2 different methods, we demonstrated an enhanced deformability of their circulating red blood cells, that likely stems from the more efficient removal of the less deformable ones. This enhanced deformability was found to be inheritable based on carefully collected family links and refined analysis of genetic markers.Implications of all the available evidenceOur findings indicate that genes potentially driving the filtration of red blood cells by the spleen likely influence how subjects in specific groups in Africa and elsewhere react to malaria. While most previous hypotheses pointed to conventional immunological mechanisms as the trigger, we propose that a simple physiological mechanism that controls the quality of red blood cells may drive natural protection from malaria even before the intervention of immunological cells. A better understanding of these processes is of great importance in the context of malaria elimination efforts.These findings may also have an impact on the understanding of other red blood cell-related disorders, such as inherited red cell diseases, in which splenic filtration of abnormal red blood cells may precipitate splenic complications.

show abstract

“…Our lead SNP (rs149514849) may influence the expression of CD44, a pleiotropic glycoprotein involved in cell-cell interactions, cell adhesion and migration, and has a role in phagocytosis by macrophages. 82 , 83 Through our mapping strategy, we also identified CD59, whose expression is decreased on Plasmodium -infected erythrocytes, which may promote erythrophagocytosis. 84 LMO2 enhances erythropoiesis, 85 and IL1RAP upregulates the expression of the "don't eat me" signal CD47 to inhibit macrophage phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

Henry

Volle

Akpovi³

et al. 2022

eBioMedicine

View full text Add to dashboard Cite

Anti-inflammatory activity of CD44 antibodies in murine immune thrombocytopenia is mediated by Fcγ receptor inhibition

Cited by 9 publications

References 59 publications

ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia

ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia

Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

Splenic clearance of rigid erythrocytes as an inherited mechanism for splenomegaly and natural resistance to malaria

Contact Info

Product

Resources

About