Dataset Information

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

ABSTRACT: Immune checkpoint receptors, including Sialic-acid-binding immunoglobulinlike 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 TNFa secretion in U937 cells, primary monocytes, and macrophages following Poly(I:C) stimulation. Mechanistically, QA79 triggers rapid FcgRindependent 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 NFkB 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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Bo Yang

PROVIDER: PXD075217 | JPOST Repository | Thu Mar 05 00:00:00 GMT 2026

REPOSITORIES: jPOST

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			Action	DRS
	20241001_BYCL_Siglec7_15_S3-B7_1_6014.d.zip	Other
	20241001_BYCL_Siglec7_17_S3-C1_1_6016.d.zip	Other
	20241001_BYCL_Siglec7_1_S3-A1_1_6000.d.zip	Other
	20241001_BYCL_Siglec7_23_S3-C7_1_6025.d.zip	Other
	20241001_BYCL_Siglec7_7_S3-A7_1_6006.d.zip	Other

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Project description:The model is first model of tissue level cellular immune responses to H. pylori in the publication, "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas. Abstract: Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

Project description:The model is the second model of the publication "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" published in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas. Abstract: Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

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

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