TREM1: A pivotal myeloid receptor target for treating autoimmune disorders and cancer.

• Gene Information: TREM1 is a transmembrane glycoprotein belonging to the immunoglobulin superfamily. TREM1 is located on chromosome 6p21.1 and it functions as a critical activating receptor on myeloid cells, essential for amplifying inflammatory cascades and modulating immune responses across various pathological conditions.
• Protein Expression: TREM1 is predominantly expressed on the surface of myeloid cells, including circulating neutrophils, inflammatory monocytes, and tumor-associated macrophages.
• Signaling Pathway: Upon ligand engagement, TREM1 associates with the ITAM-containing adapter DAP12 to recruit SYK kinase. This initiates downstream phosphorylation cascades driving NF-κB activation, which triggers massive pro-inflammatory cytokine release in autoimmunity while amplifying myeloid-driven suppressive networks in cancer.
• Therapeutic Targeting: TREM1 is a key target for therapeutic antagonists. In autoimmune diseases, blocking TREM1 attenuates pathological hyperinflammation and tissue damage. In oncology, neutralizing TREM1 reprograms tumor-associated macrophages to relieve immunosuppression, reinvigorating robust anti-tumor responses and enhancing immunotherapy efficacy.

TREM1

• The exons 1-4 of mouse Trem1 gene that encode signal peptide and extracellular domain are replaced by human counterparts in B-hTREM1/hPGLYRP1 mice.
• The genomic region of mouse Trem1 gene that encodes transmembrane domain and cytoplasmic portion is retained. The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained. The human TREM1 expression is driven by endogenous mouse Trem1 promoter, while mouse Trem1 gene transcription and translation will be disrupted.

PGLYRP1

• The exons 1-3 of mouse Pglyrp1 gene that encode the whole molecule (ATG to STOP codon), including 3’UTR were replaced by human counterparts in B-hTREM1/hPGLYRP1 mice.
• The promoter and 5’UTR region of the mouse gene are retained. The human PGLYRP1 expression is driven by endogenous mouse Pglyrp1 promoter, while mouse Pglyrp1 gene transcription and translation will be disrupted.

• Human TREM1 was exclusively detectable in neutrophils and CD11b+ cells of homozygous B-hTREM1/hPGLYRP1 mice but not wild-type C57BL/6 mice.

Strain specific TREM1 expression analysis in homozygous B-hTREM1/hPGLYRP1 mice by flow cytometry. Splenocytes were collected from wild-type C57BL/6 mice (+/+) and homozygous B-hTREM1/hPGLYRP1 mice (H/H;H/H), and analyzed by flow cytometry with species-specific anti-mouse TREM1 antibody (Mouse TREM-1 PE-conjugated Antibody, R&D, FAB1187P) and anti-human TREM1 antibody (APC anti-human CD354 (TREM-1) Antibody, Biolegend, 314909). Mouse TREM1 was only detectable in neutrophils and CD11b+ cells of wild-type C57BL/6 mice. Human TREM1 was exclusively detectable in neutrophils and CD11b+ cells of homozygous B-hTREM1/hPGLYRP1 mice but not in wild-type mice.

• Human soluble TREM1 was exclusively detectable in homozygous B-hTREM1/hPGLYRP1 mice.

Strain specific TREM1 expression analysis in homozygous B-hTREM1/hPGLYRP1 mice by ELISA. Serum was collected from wild-type C57BL/6 (+/+) and homozygous B-hTREM1/hPGLYRP1 mice (H/H;H/H) stimulated with 20 μg/mouse LPS in vivo for 2 hrs. Expression level of mouse and human TREM1 were analyzed by ELISA (anti-mouse TREM1 ELISA kit: R&D, MTRM10; anti-human TREM1 ELISA kit: R&D, DTRM10C). Mouse TREM1 was only detectable in wild-type C57BL/6 mice. Human TREM1 was exclusively detectable in homozygous B-hTREM1/hPGLYRP1 mice, which indicating that mouse matrix metalloproteinase (MMP) was capable of proteolytically cleaving human TREM1, and inducing the release of soluble TREM1. Values are expressed as mean ± SEM. ND: not detectable.

• Human PGLYRP1 was exclusively detectable in homozygous B-hTREM1/hPGLYRP1 mice.

Strain specific PGLYRP1 expression analysis in homozygous B-hTREM1/hPGLYRP1 mice by ELISA. Serum was collected from wild-type C57BL/6 (+/+) and homozygous B-hTREM1/hPGLYRP1 mice (H/H;H/H) stimulated with or without LPS in vivo for 2 hrs. Expression level of mouse and human PGLYRP1 were analyzed by ELISA (anti-mouse PGLYRP1 ELISA kit: OriGene, EA102442; anti-human PGLYRP1 ELISA kit: R&D, DY2590). Mouse PGLYRP1 was only detectable in wild-type C57BL/6 mice. Human PGLYRP1 was exclusively detectable in homozygous B-hTREM1/hPGLYRP1 mice. Values are expressed as mean ± SEM.

Experimental schedule for DSS induced acute colitis in B-hTREM1/hPGLYRP1 mice. The homozygous B-hTREM1/hPGLYRP1 mice were divided into four groups. The normal controls were administered drinking water for 7 consecutive days, the treatment groups were administered 3.5% DSS solution for 7 consecutive days.

• TREM1-318-IgG1.3f (in house) treatment efficiently improved DSS induced acute colitis.

B-hTREM1/hPGLYRP1 mice were administered DSS in drinking water for 7 consecutive days. The homozygous B-hTREM1/hPGLYRP1 mice were divided into four groups. The normal controls were administered drinking water for 7 consecutive days, the treatment groups were administered 3.5% DSS solution for 7 consecutive days. TREM1-318-IgG1.3f (in house) at a dose of 10 or 25 mpk was administered to the treatment groups. (A) Body weight change. (B) DAI score. (C) Colon index. (D) Colon photo. Values are expressed as mean ± SEM. Significance was determined by two-way ANOVA test.  *P < 0.05, **P < 0.01, ***P < 0.001.

• TREM1-318-IgG1.3f (in house) reduced inflammatory infiltration and epithelial damage in colon tissue.

B-hTREM1/hPGLYRP1 mice were administered DSS in drinking water for 7 consecutive days. The homozygous B-hTREM1/hPGLYRP1 mice were divided into four groups. The normal controls were administered drinking water for 7 consecutive days, the treatment groups were administered 3.5% DSS solution for 7 consecutive days. TREM1-318-IgG1.3f (in house) at a dose of 10 or 25 mpk was administered to the treatment groups. (A) H&E staining of colon tissue. (B) Pathological score. Values are expressed as mean ± SEM. Significance was determined by one-way ANOVA test.  *P < 0.05, **P < 0.01, ***P < 0.001.

• TREM1-318-IgG1.3f (in house) decreased protein expression of intestinal inflammatory factors.

B-hTREM1/hPGLYRP1 mice were administered DSS in drinking water for 7 consecutive days. The homozygous B-hTREM1/hPGLYRP1 mice were divided into four groups. The normal controls were administered drinking water for 7 consecutive days, the treatment groups were administered 3.5% DSS solution for 7 consecutive days. TREM1-318-IgG1.3f (in house) at a dose of 10 or 25 mpk was administered to the treatment groups. On day 7, the mice were sacrificed, serum were collected for protein analysis of pro-inflammatory factors mouse IL-6 and TNF-α. One-way ANOVA was used for multiple comparisons, with each group compared to G2. Values are expressed as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001.