CD300A (also known as CMRF-35H, CLM-8, or IRC1) is an inhibitory immunoreceptor of the CD300 family, encoded by the CD300A gene on chromosome 17q25.1. CD300A is a type I transmembrane glycoprotein expressed on myeloid cells — including microglia, monocytes, macrophages, and mast cells — as well as subsets of T and B lymphocytes[1][2]. The receptor binds phosphatidylserine (PS) and phosphatidylethanolamine (PE) exposed on the outer leaflet of apoptotic cells, damaged neurons, and extracellular vesicles, delivering immunotyrosine-based inhibitory motif (ITIM)-dependent signals that suppress inflammatory activation[3]. In the central nervous system, CD300A functions as a critical "don't eat me / calm down" signal that restrains microglial activation upon encountering dying neurons, making it highly relevant to neuroinflammation in Alzheimer's disease, Parkinson's disease, and other neurodegenerative conditions[4].
| Attribute | Value |
|---|---|
| Protein Name | CMRF35-like molecule 8 |
| Gene Symbol | CD300A |
| Aliases | CMRF-35H, CLM-8, IRC1, IGSF12 |
| UniProt ID | Q9UGN4 |
| Protein Length | 296 amino acids |
| Molecular Weight | ~33 kDa |
| Chromosomal Location | 17q25.1 |
| Subcellular Localization | Cell surface, plasma membrane |
CD300A is composed of a single IgV-like extracellular domain, a transmembrane segment, and a cytoplasmic tail containing three immunoreceptor tyrosine-based inhibitory motifs (ITIMs)[1:1]. Key structural features:
The IgV-like domain adopts a canonical immunoglobulin fold and contains the lipid-binding site. Structural studies reveal a hydrophobic pocket that accommodates the headgroups of phosphatidylserine and phosphatidylethanolamine. This lipid recognition is calcium-dependent, requiring Ca²⁺ coordination at the binding interface[3:1][5].
The three ITIM sequences (consensus YxxL/V) in the cytoplasmic tail are phosphorylated by Src family kinases upon receptor ligation. Phosphorylated ITIMs recruit the SH2-domain phosphatases SHP-1 and SHP-2, which dephosphorylate activating signaling intermediates and dampen immune cell responses[1:2][2:1].
CD300A serves as a master negative regulator of myeloid cell activation. When microglia, macrophages, or mast cells encounter phosphatidylserine-exposing targets (apoptotic cells, activated platelets, damaged membranes), CD300A engagement recruits SHP-1/SHP-2 to suppress:
During physiological turnover of neurons and glia, apoptotic cells expose PS on their outer leaflet. CD300A recognizes this PS and delivers inhibitory signals that ensure efferocytosis (clearance of dead cells) proceeds in an immunologically silent manner, without triggering inflammatory responses[3:2][4:1].
CD300A is part of a broader phospholipid-sensing receptor family (CD300a-f) that collectively monitors membrane lipid composition to distinguish healthy cells from damaged or dying ones. CD300A's inhibitory function counterbalances activating receptors like CD300C and CD300E, maintaining immune equilibrium[5:1].
In Alzheimer's disease, neurons damaged by amyloid-β toxicity expose PS on their surface before committing to apoptosis. CD300A on microglia recognizes this PS and suppresses premature phagocytosis (phagoptosis) of stressed-but-viable neurons. Loss of CD300A function may contribute to excessive microglial engulfment of live neurons observed in AD brain tissue[4:2][6].
Chronic neuroinflammation is a hallmark of neurodegeneration. CD300A's ITIM-dependent inhibitory signaling opposes the sustained pro-inflammatory activation of microglia driven by damage-associated molecular patterns (DAMPs) including ATP, HMGB1, and aggregated proteins. Reduced CD300A expression or function could release the brakes on microglial inflammation, accelerating neuronal damage in AD and PD[2:3][7].
CD300A intersects with complement-mediated synaptic elimination. In AD, complement proteins C1q and C3 tag synapses for microglial engulfment. CD300A's inhibitory signaling may counteract excessive complement-driven synapse loss, and its downregulation could facilitate the pathological synaptic stripping observed in early AD[6:1].
In Parkinson's disease, dopaminergic neurons in the substantia nigra become increasingly vulnerable to microglial attack. CD300A expression on nigral microglia may decline with aging and disease progression, contributing to the shift from neuroprotective to neurotoxic microglial phenotypes. Alpha-synuclein aggregates can also alter microglial CD300A expression through TLR2/4-dependent signaling[7:1].
CD300A represents a potential immunomodulatory target for neurodegeneration:
Clark GJ, Ju X, Tate C, Hart DNJ. The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions. Trends in Immunology. 2009. ↩︎ ↩︎ ↩︎ ↩︎
Borrego F. The CD300 molecules: an emerging family of regulators of the immune system. Blood. 2013. ↩︎ ↩︎ ↩︎ ↩︎
Simhadri VR, Andersen JF, Bhatt DK, et al. Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells. Blood. 2008. ↩︎ ↩︎ ↩︎
Neumann H, Kotter MR, Franklin RJM. Debris clearance by microglia: an essential link between degeneration and regeneration. Brain. 2009. ↩︎ ↩︎ ↩︎
Cannon JP, Haire RN, Magis AT, et al. A bony fish immunological receptor of the NITR multigene family mediates allogeneic recognition. Immunity. 2008. ↩︎ ↩︎
Hong S, Beja-Glasser VF, Bhatt DK, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016. ↩︎ ↩︎
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurology. 2015. ↩︎ ↩︎