Surface toll-like receptor 9 on immune cells and its immunomodulatory effect

Abstract

Toll like receptor 9 (TLR9) has been considered as a crucial intracellular pattern recognition receptor in the immune system, which can directly or indirectly mediate innate and adaptive immune responses by recognizing CpG DNA in endosomes to initiate its downstream signaling. However, TLR9 can also be expressed on the membrane surface of some immune and non-immune cells, called surface TLR9 (sTLR9), which covers the TLR9 and its immunomodulatory role with a mysterious veil. In this review, we mainly focus on the sTLR9 expressed on neutrophils, B cells and erythrocytes, and its immunomodulatory roles displayed alone or in coordination with endosomal TLR9 (eTLR9), providing a theoretical reference for the application of its modulators.

Keywords: B cells; erythrocytes; immunomodulation; neutrophils; surface toll-like receptor 9.

Figure 1

A mode diagram for the trafficking of sTLR9 and intracellular TLR9. 1) TLR9 is synthesized in the ER, and its proper folding require ER luminal chaperones gp96 and PRAT4A. 2) TLRO requires the ER membrane protein Unc93B1 to exit the ER. The TLR9 in the ER migrates outward via the Golgi secretion pathway and is loaded into COPII⁺ vesicles for further migration to the cell membrane surface or endolysosomal membrane. 3) Unc93B1 and TLR9 traffic together to the cell surface, and then Unc93B1 recruits AP2 (an adaptor protein complex that promotes endocytosis of cell surface molecules) to traffic TLR9 from the cell surface to endolysosomes. 4) In parallel, the TLR9 ligand, CpG ODN, is endocytosed in a clathrin-dependent manner and meets its cognate receptor. 5) and 6) Here, the pathway bifurcates. The migration of TLR9 to the IRF-SE induces the production of type I IFNs, and the localization to the NF-κB-SE induces the expression of proinflammatory cytokines. 7) In human pDCs, BAD-LAMP facilitates the trafficking of TLR9 from the IRF-SE to the NF-B-SE. g96, glycoprotein 96; PRAT4A, protein associated with TLR4A; AP2, adaptor protein 2; IRF-SE, IRF-signaling endosome; NF-κB-SE, NF-κB-signaling endosome; BAD-LAMP, brain and DC-associated LAMP-like molecule.

Figure 2

Schematic diagram of immunomodulatory effect of sTLR9 on immune cells. The immunomodulatory effect of sTLR9 on neutrophils (A), B cells (B) and erythrocytes (C). ICAMI, intercellular cell adhesion molecule 1; PD-LI, programmed death ligand 1; TNFα, tumor necrosis factor α: SIRPa, signal regulatory protein α. Dashed lines indicate that direct evidence is still absent, but present data support the hypothesis.