Evidence for C1q-mediated crosslinking of CD33/LAIR-1 inhibitory immunoreceptors and biological control of CD33/LAIR-1 expression

• Published in: Scientific reports 2017-03, Vol.7 (1), p.270-13, Article 270
• Main Authors: Son, Myoungsun, Diamond, Betty, Volpe, Bruce T., Aranow, Cynthia B., Mackay, Meggan C., Santiago-Schwarz, Frances
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/21; 13/31; 13/51; 14/1; 14/10; 14/19; 14/63; 38/1; 631/250/127; 631/250/38; 631/80/304; 692/4023/1670; 82/29; 82/79; 96/1; Acids; Biological control; Cell activation; Collagen; Complement component C1q; Cytokines; Growth factors; Humanities and Social Sciences; Immunological tolerance; Inflammation; Ligands; Lupus; Macrophage colony-stimulating factor; Medical research; Monocytes; multidisciplinary; Proteins; Science; Science (multidisciplinary); Systemic lupus erythematosus
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-00290-w

C1q collagen-like region (CLR) engaging and activating the LAIR-1 inhibitory immunoreceptor represents a non-complement mechanism for maintaining immune quiescence. Given the binding promiscuity of C1q’s globular region (gC1q), we hypothesized that C1q concurrently associates with distinct inhibitory immunoreceptors to produce C1q-mediated modulatory networking. Like LAIR-1, CD33 inhibitory immunoreceptors are highly expressed on monocytes. Binding CD33 restricts cell activation/differentiation; however, natural ligands for CD33 remain elusive. CD33 has IgC2-like domains potentially recognized by gC1q. Thus, we asked whether C1q binds to CD33 and if C1q mediates CD33/LAIR-1 crosslinking. Our findings demonstrate that C1q and gC1q interact with CD33 to activate its inhibitory motifs, while CLR does not. Whole C1q is required to crosslink CD33 and LAIR-1 and concurrently activate CD33/LAIR-1 inhibitory motifs. While C1q binds CD33C2 domains, decreased C1q-CD33 interactions resulting from sialic acid masking of CD33C2 domains suggests a process for regulating C1q-CD33 activity. Consistent with defective self-tolerance, CD33/LAIR-1 expression is reduced in systemic lupus erythematosus (SLE) myelomonocytes. The anti-inflammatory cytokine M-CSF, but not DC growth factors, sustains CD33/LAIR-1 expression on both healthy and SLE cells suggesting further biological control of C1q-CD33/LAIR-1 processes.