Article

Recognition and functional activation of the human IgA receptor (FcalphaRI) by C-reactive protein.

Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 03/2011; 108(12):4974-9. DOI: 10.1073/pnas.1018369108
Source: PubMed

ABSTRACT C-reactive protein (CRP) is an important biomarker for inflammatory diseases. However, its role in inflammation beyond complement-mediated pathogen clearance remains poorly defined. We identified the major IgA receptor, FcαRI, as a ligand for pentraxins. CRP recognized FcαRI both in solution and on cells, and the pentraxin binding site on the receptor appears distinct from that recognized by IgA. Further competitive binding and mutational analysis showed that FcαRI bound to the effector face of CRP in a region overlapping with complement C1q and Fcγ receptor (FcγR) binding sites. CRP cross-linking of FcαRI resulted in extracellular signal-regulated kinase (ERK) phosphorylation, cytokine production, and degranulation in FcαRI-transfected RBL cells. In neutrophils, CRP induced FcαRI surface expression, phagocytosis, and TNF-α secretion. The ability of CRP to activate FcαRI defines a function for pentraxins in inflammatory responses involving neutrophils and macrophages. It also highlights the innate aspect of otherwise humoral immunity-associated antibody receptors.

0 Followers
 · 
130 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Monocyte-derived, fibroblast-like cells called fibrocytes are associated with fibrotic lesions. The plasma protein serum amyloid P component (SAP; also known as pentraxin-2, PTX2) inhibits fibrocyte differentiation in vitro, and injections of SAP inhibit fibrosis in vivo. SAP is a member of the pentraxin family of proteins that includes C-reactive protein (CRP; PTX1) and pentraxin-3 (PTX3). All three pentraxins are associated with fibrosis, but only SAP and CRP have been studied for their effects on fibrocyte differentiation. We find that compared to SAP and CRP, PTX3 promotes human and murine fibrocyte differentiation. The effect of PTX3 is dependent on FcγRI. In competition studies, the fibrocyte-inhibitory activity of SAP is dominant over PTX3. Binding competition studies indicate that SAP and PTX3 bind human FcγRI at different sites. In murine models of lung fibrosis, PTX3 is present in fibrotic areas, and the PTX3 distribution is associated with collagen deposition. In lung tissue from pulmonary fibrosis patients, PTX3 has a widespread distribution, both in unaffected tissue and in fibrotic lesions, whereas SAP is restricted to areas adjacent to vessels, and absent from fibrotic areas. These data suggest that the relative levels of SAP and PTX3 present at sites of fibrosis may have a significant effect on the ability of monocytes to differentiate into fibrocytes.
    PLoS ONE 10(3):e0119709. DOI:10.1371/journal.pone.0119709 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Evidence suggests that sickle cell disease (SCD) is associated with a chronic inflammatory state. C-reactive protein (CRP) is known to modulate inflammation. Its role in the chronic inflammation of SCD may make it valuable as a therapeutic target.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The plasma protein serum amyloid P (SAP) reduces neutrophil adhesion, inhibits the differentiation of monocytes into fibroblast-like cells called fibrocytes, and promotes phagocytosis of cell debris by macrophages. Together, these effects of SAP reduce key aspects of inflammation and fibrosis, and SAP injections improve lung function in pulmonary fibrosis patients. SAP functions are mediated, in part, by FcγRs, but the contribution of each FcγR is not fully understood. We found that aa Q55 and E126 in human SAP affect human fibrocyte differentiation and SAP binding to FcγRI. E126, K130, and Q128 affect neutrophil adhesion and SAP affinity for FcγRIIa. Q128 also affects phagocytosis by macrophages and SAP affinity for FcγRI. All the identified functionally significant amino acids in SAP form a binding site that is distinct from the previously described SAP-FcγRIIa binding site. Blocking FcγRI with an IgG-blocking Ab reduces the SAP effect on fibrocyte differentiation, and ligating FcγRIIa with Abs reduces neutrophil adhesion. Together, these results suggest that SAP binds to FcγRI on monocytes to inhibit fibrocyte differentiation, and binds to FcγRIIa on neutrophils to reduce neutrophil adhesion.
    The Journal of Immunology 07/2014; 193(4). DOI:10.4049/jimmunol.1400281 · 5.36 Impact Factor

Full-text (2 Sources)

Download
68 Downloads
Available from
May 29, 2014