Evidence for C1q-mediated crosslinking of CD33/LAIR-1 inhibitory immunoreceptors and biological control of CD33/LAIR-1 expression.
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.
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
Myoungsun
0000-0002-0655-3859
M
Son
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
Betty
B
Diamond
Center for Biomedical Science, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
Bruce T
BT
Volpe
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
Cynthia B
CB
Aranow
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA.
Meggan C
MC
Mackay
Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, 11030, USA. Fsantiago1@northwell.edu.
Frances
0000-0001-9393-327X
F
Santiago-Schwarz
D002478:Cells, Cultured; D015922:Complement C1q / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000378:metabolism*; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000378:metabolism*
C571163:CD33 protein, human; D011971:Receptors, Immunologic; D063268:Sialic Acid Binding Ig-like Lectin 3; C108073:leukocyte-associated immunoglobulin-like receptor 1; D015922:Complement C1q