# Siglec-7 inhibits TLR3-induced pro-inflammatory cytokine production from human monocytes and macrophages

## TL;DR

Siglec-7 limits inflammation by inhibiting TLR3 signaling in human immune cells, offering a new therapeutic target for autoimmune diseases.

## Contribution

Siglec-7 is shown to directly inhibit TLR3 signaling in myeloid cells via endolysosomal co-localization.

## Key findings

- Siglec-7 crosslinking reduces TNFα production in monocytes and macrophages after TLR3 activation.
- Siglec-7 co-localizes with TLR3 in endolysosomes, suppressing NF-κB phosphorylation.
- Siglec-7 acts as a negative regulator of TLR3-driven inflammation in human myeloid cells.

## Abstract

Immune checkpoint receptors, including Sialic-acid-binding immunoglobulin-like lectins (Siglecs), are critical regulators of immune homeostasis. Siglecs can serve as negative regulators of Toll-like receptor (TLR) signaling, promoting the resolution of inflammatory signaling through feedback inhibition mechanisms. Previous studies demonstrated that Siglec-E, the murine homolog of the human inhibitory receptor Siglec-7, negatively regulates TLR4 signaling by controlling receptor endocytosis. This regulatory mechanism suggests that Siglec-7 may also limit TLR signaling. Here we reveal a novel mechanism whereby Siglec-7 represses endosomal TLR3 activation, compared to other TLRs, in human myeloid cells. Crosslinking Siglec-7 with antibody clone QA79 significantly reduced TNFα secretion in U937 cells, primary monocytes, and macrophages following Poly(I:C) stimulation. Mechanistically, QA79 triggers rapid FcγR-independent internalization and endolysosomal trafficking of surface Siglec-7, which enables the direct co-localization of Siglec-7 with TLR3 within the endolysosome. This co-localization between Siglec-7 and TLR3 suppresses NF-κB phosphorylation, a key pro-inflammatory signaling node downstream of TLR3. These findings establish a previously unrecognized negative regulatory role of Siglec-7 for TLR3-mediated inflammation in myeloid cells, where a disrupted interaction could contribute to autoimmune disease pathogenesis. Targeting this pathway represents a promising therapeutic approach for TLR3-driven autoimmune diseases.