Figure 2.

Microglial parainflammatory regulation: Microglia remove toxic metabolites, apoptotic cells, and oxidative debris while maintaining the health of photoreceptors and retinal cells in a process called parainflammation. (1) Parainflammation is initiated by pattern recognition receptors found on (2) M0 microglia such as TLR, TREM2, CX3CR1, NLRP3, and CD36, which use these receptors to bind and sense toxins, apoptotic cells, damage, and pathogen-associated molecular patterns. Once microglia are activated, they polarize to the (3) M1 like state, (4) secrete proinflammatory cytokines, and (5) migrate to the areas of stressed RPE cells and photoreceptors. (6) Upon activation, neuropilin-2-PSA and E-selectin ligand 1-PSA are secreted by these activated microglia. (6) The PSA on these glycoproteins binds Siglecs on activated microglial cells (7) to polarize them into the M2c healing state (8), which releases growth factors to protect and regenerate the stressed photoreceptors and RPE cells. (9) This homeostatic maintenance function of microglial parainflammation, if not adequately modulated with sialic acid checkpoint regulation, will result in recruitment of peripheral blood monocytes and AMD disease progression. (10) A PSA-nanoparticle (PSA-NP) mimics E-selectin ligand 1 PSA and Neuropilin 2-PSA to (7) polarize M1 activated microglia into the M2c healing state.