Inhibition of SPI1 by ADAP Regulates S100A8/A9 Signaling in Macrophages to Control the Development of Colitis
Open accessAbstract
Although the immune adaptor protein ADAP (adhesion and degranulation adaptor protein) plays a critical role in regulating macrophage inflammatory responses, its impact on intestinal inflammation remains elusive. This study reveals that ADAP-deficient mice have increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and intestinal inflammation due to upregulation of S100A8/A9 expression (also known as MRP8 and MRP14, respectively) both in vivo and in vitro. Mechanistically, ADAP promotes proteasomal degradation of the transcription factor SPI1 (SPI-1 proto-oncogene) via the E3 ubiquitin ligase FBXW7 (F-box and WD repeat domain-containing 7)-mediated ubiquitination. ADAP deficiency increases SPI1 expression for transcription of the S100A8/A9 promoter. Blockade of SPI1 effectively prevents colitis-induced S100A8/A9 upregulation in macrophages. Thus, our findings highlight the potential link between ADAP and intestinal inflammation, while also paving the way for therapeutic interventions targeting the ADAP-SPI1-S100A8/A9 signaling axis in inflammatory colitis.
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Written from the paper’s full text.
TL;DR
ADAP deficiency exacerbates DSS-induced colitis in mice by increasing macrophage S100A8/A9 expression through SPI1. ADAP normally promotes FBXW7-mediated ubiquitination and proteasomal degradation of SPI1, limiting S100A8/A9–NF-κB inflammatory signaling.
Key findings
- ADAP expression was elevated in colonic tissues from ulcerative colitis patients and DSS-induced colitis mice, and in DSS-treated WT mice at protein and mRNA levels.
- ADAP-deficient mice showed greater DSS colitis severity, including increased body weight loss, colon shortening, higher pathological scores, and elevated colonic and serum TNF-α, IL-1β, and IL-6; clodronate-mediated macrophage depletion reversed the exacerbated inflammation.
- DSS-treated ADAP-deficient mice had 1,041 differentially expressed genes versus WT (699 upregulated, 342 downregulated), with NF-κB pathway enrichment and increased S100A8/A9; ADAP knockdown in LPS-stimulated RAW264.7 macrophages also increased S100A8/A9 and NF-κB signaling.
- Mechanistically, ADAP deficiency increased SPI1 protein without affecting Spi1 mRNA; FBXW7 mediated K48-linked polyubiquitination and proteasomal degradation of SPI1, and SPI1 knockdown suppressed S100A8/A9 transcription and NF-κB signaling.
Methods
- Eight-week-old male WT and Adap−/− mice were co-housed for 2 weeks, then given 3% DSS for 7 days (n = 6 per group); macrophage depletion used 200 µL clodronate liposomes intraperitoneally on DSS days 1, 2, and 5.
- In vitro studies used RAW264.7 WT/ADAP-knockdown cells and HEK293T cells with LPS (1 µg/mL, 24 h), MG132 or chloroquine (10 µM), SPI1 siRNA, luciferase reporter, CUT&RUN, Co-IP, and ubiquitin mutants K48R/K63R.
- Colonic RNA-seq used DEG cutoff |log₂FC| > 1 and adjusted p < 0.05, with GO/KEGG/GSEA; statistics used unpaired two-tailed Student’s t-test or one-way/two-way ANOVA with Tukey’s or Sidak’s tests.
Limitations
- Stated: global ADAP knockout may include contributions from non-myeloid cells; insufficient viable lamina propria macrophages for transcriptomic sequencing led to whole-colon RNA-seq integrated with published datasets; the mechanism by which ADAP upregulates FBXW7 remains unclear and is hypothesized to involve epigenetic regulation.
- Evident from the text: experiments used only 8-week-old male mice, so sex- and age-specific effects were not assessed, and the colitis work used an acute DSS model rather than chronic or human interventional validation.
Model-written summary. Check it against the paper before relying on it.
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Cites
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Claims the paper makes
21 of 30 cited sources checked · 12 supported · 0 flagged · accuracy not yet measured
- Premisecitation
SPI1 functions as a transcriptional activator of S100A8/A9.
“SPI1 functions as a transcriptional activator of S100A8/A9.”
- Also stated in: § Discussion · plain
“Importantly, SPI1 has also been associated with ulcerative colitis (UC) [27] and shown to transcriptionally regulate S100A8/A9 expression [28–30].”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [28] Swindell, W.R., A. Johnston, X. Xing, A. Little, P. Robichaud, J.J. Voorhees, et al. 2013. Robust shifts in S100a9 expression with aging: A novel mechanism for chronic inflammation. Scientific Reports 3: 1215. source
The Discussion identifies SPI1/PU.1 as an activator of S100a9 expression and reports supporting motif associations and prior experimental evidence. It does not establish SPI1 as a transcriptional activator of S100a8; the paper says S100a8 and S100a9 may share regulatory mechanisms but are not always co-expressed. The cited claim therefore extends the supported S100a9 point to S100A8/A9. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [29] Liu, X., C. Zhang, Z. Zhang, Z. Zhang, W. Ji, S. Cao, et al. 2017. E26 transformation-specific transcription factor ETS2 as an oncogene promotes the progression of hypopharyngeal cancer. Cancer Biotherapy & Radiopharmaceuticals 32 (9): 327–334. source
- cites [30] Cai, X., L. Hong, Y. Liu, X. Huang, H. Lai, and L. Shao. 2022. Salmonella pathogenicity island 1 knockdown confers protection against myocardial fibrosis and inflammation in uremic cardiomyopathy via down-regulation of S100 calcium binding protein A8/A9 transcription. Renal Failure 44 (1): 1819–1832. source
- Also stated in: § Discussion · plain
- Premisecitation
During colonic inflammation, elevated S100A8/A9 levels are detectable in both serum and colonic tissues.
“During colonic inflammation, elevated S100A8/A9 levels are detectable in both serum and colonic tissues [23]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Okada, K., H. Itoh, and M. Ikemoto. 2020. Circulating S100A8/A9 is potentially a biomarker that could reflect the severity of experimental colitis in rats. Heliyon 6 (2): e03470. source
The Results section ('Changes in the serum levels'; page unavailable) reports that serum S100A8/A9 rose markedly in rats with experimental colitis. The Discussion (page unavailable) says the heterodimer was expressed in macrophages in rectal tissue, but the paper does not establish elevated S100A8/A9 levels in colonic tissue. That part of the claim goes beyond the evidence in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
SPI1 has been associated with ulcerative colitis.
“Importantly, SPI1 has also been associated with ulcerative colitis (UC) [27] and shown to transcriptionally regulate S100A8/A9 expression [28–30].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] Arai, N., T. Kudo, K. Tokita, R. Kyodo, M. Sato, E. Miyata, et al. 2022. Expression of oncogenic molecules in pediatric ulcerative colitis. Digestion 103 (2): 150–158. source
- Findingown data
SPI1 is primarily degraded via the proteasomal pathway in ADAP-knockdown macrophages.
“Pretreatment with the proteasomal inhibitor MG132 or the autophagy inhibitor chloroquine (CQ) indicated that SPI1 is primarily degraded via the proteasomal pathway (Fig. 8A).”
Quote in the paperSubstantial claim - Findingown data
UbiBrowser 2.0 predicted FBXW7 and USP7 as potential SPI1-interacting proteins.
“To identify the regulators of SPI1 turnover, we used UbiBrowser 2.0, which predicted FBXW7 (an E3 ubiquitin ligase) and USP7 (a deubiquitinase) as potential SPI1-interacting proteins.”
Quote in the paperNot a substantial claim
- Findingown data
SPI1 knockdown suppresses NF-κB signaling upon LPS stimulation in RAW264.7 macrophages.
“Moreover, SPI1 knockdown significantly suppressed NF-κB signaling upon LPS stimulation in RAW264.7 macrophages (Fig. 7H).”
Quote in the paperSubstantial claim - Findingown data
K48, but not K63, is the primary ubiquitination site on SPI1.
“Mutagenesis analysis revealed that K48, but not K63, served as the primary ubiquitination site, indicating that K48-linked polyubiquitination drives SPI1 proteasomal degradation (Fig. 8D).”
Quote in the paperSubstantial claim - Findingown data
Inhibition of SPI1 activity attenuates S100A8/A9 transcription.
“Consistently, luciferase reporter assays and analyses of S100A8/A9 expression demonstrated that inhibition of SPI1 activity attenuated S100A8/A9 transcription (Fig. 7G).”
Quote in the paperSubstantial claim - Findingown data
ADAP knockdown in RAW264.7 macrophages results in excessive activation of S100A8/A9 signaling upon LPS stimulation.
“Supporting this notion, in vitro experiments using RAW264.7 macrophages revealed that ADAP knockdown resulted in excessive activation of S100A8/A9 signaling upon LPS stimulation (Fig. 6D-E).”
Quote in the paperSubstantial claim - Findingown data
ADAP expression is predominantly localized to macrophages during the inflammatory phase in UC scRNA-seq data.
“Within the same dataset, ADAP expression was markedly increased during the inflammatory phase (Fig. 3A) and predominantly localized to macrophages (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
ADAP-knockdown macrophages have markedly reduced FBXW7 expression compared with WT controls.
“Notably, ADAP-knockdown macrophages exhibited markedly reduced FBXW7 expression compared with WT controls (Fig. 8B; Suppl. Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
ADAP deficiency exacerbated DSS-induced colonic inflammation.
“Our results showed that ADAP deficiency exacerbated DSS-induced colonic inflammation.”
Quote in the paperSubstantial claim - Findingown data
The NF-κB signaling pathway is activated in DSS-induced colitic ADAP-deficient mice.
“Functional enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) highlighted the NF-κB signaling pathway as a key node in the exacerbated inflammatory process observed in ADAP-deficient mice (Fig. 5C-D).”
- Also stated in: § ADAP Deficiency Exacerbates Colitis by Hyperactivating the NF-κB Signaling Pathway · boosted
“Consistently, gene set enrichment analysis (GSEA) further confirmed robust activation of the NF-κB pathway in DSS-induced colitic ADAP-deficient mice (Fig. 5E).”
Quote in the paperSubstantial claim - Also stated in: § ADAP Deficiency Exacerbates Colitis by Hyperactivating the NF-κB Signaling Pathway · boosted
- Findingown data
ADAP deficiency leads to elevated colonic and serum levels of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 in DSS-induced colitis.
“At the molecular level, colonic tissues from ADAP-deficient mice displayed elevated levels of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 (Fig. 2E), which was also reflected systemically by higher serum cytokine levels (Fig. 2F).”
Quote in the paperSubstantial claim - Findingown data
Macrophage depletion with clodronate liposomes alleviates the exacerbated inflammation in ADAP-deficient mice during DSS-induced colitis.
“Effective macrophage depletion alleviated the exacerbated inflammation observed in ADAP-deficient mice, as evidenced by improvements in body weight, pathological scores, mucosal damage (Fig. 4C-D), and systemic inflammatory cytokine levels (Fig. 4E).”
Quote in the paperSubstantial claim - Findingown data
FBXW7 mediates SPI1 ubiquitination.
“Co-transfection assays in HEK293T cells confirmed that FBXW7 mediates SPI1 ubiquitination (Fig. 8C).”
Quote in the paperSubstantial claim - Findingreasoning
Blockade of SPI1 prevents colitis-induced S100A8/A9 upregulation in macrophages.
“Blockade of SPI1 effectively prevents colitis-induced S100A8/A9 upregulation in macrophages.”
Quote in the paperSubstantial claim - Findingown data
In public scRNA-seq data from UC patients, ADAP is mainly expressed in immune cell clusters (T cells, macrophages, neutrophils, dendritic cells) with minimal expression in epithelial cells.
“Analysis of public scRNA-seq data from UC patients revealed that ADAP was mainly expressed in immune cell clusters, including T cells, macrophages, neutrophils, and dendritic cells—with minimal expression in epithelial cells (Suppl. Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
ADAP-deficient macrophages preferentially polarize toward the pro-inflammatory M1 phenotype.
“our preliminary data demonstrated that ADAP-deficient macrophages preferentially polarize toward the pro-inflammatory M1 phenotype”
Quote in the paperSubstantial claim - Findingown data
ADAP upregulates FBXW7 expression at both the mRNA and protein levels.
“although we demonstrated that ADAP upregulates FBXW7 expression at both the mRNA and protein levels, the underlying regulatory mechanism remains unclear (Suppl. Fig. 3B).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Impaired degradation of SPI1 in ADAP-deficient macrophages leads to increased S100A8/A9 secretion.
“Impaired degradation of SPI1 in ADAP-deficient macrophages consequently led to increased S100A8/A9 secretion and enhanced inflammatory responses.”
Quote in the paperSubstantial claim - Interpretationreasoning
Dysregulation of FBXW7 is linked to the hyperinflammatory phenotype in ADAP-knockdown macrophages.
“These findings establish FBXW7 as a critical post-translational regulator of SPI1 stability and link its dysregulation to the hyperinflammatory phenotype in ADAP-knockdown macrophages.”
Quote in the paperSubstantial claim - Interpretationown data
Impaired degradation of SPI1 in ADAP-deficient macrophages leads to enhanced inflammatory responses.
“Impaired degradation of SPI1 in ADAP-deficient macrophages consequently led to increased S100A8/A9 secretion and enhanced inflammatory responses.”
Quote in the paperSubstantial claim - Interpretationown data
ADAP deficiency amplifies the inflammatory response during colitis through aberrant activation of the NF-κB signaling cascade.
“Collectively, these findings reveal that ADAP deficiency amplifies the inflammatory response during colitis through aberrant activation of the NF-κB signaling cascade.”
Quote in the paperSubstantial claim - Interpretationreasoning
The pronounced upregulation of S100A8/A9 in ADAP-deficient colitis mice likely reflects aggravated intestinal inflammation.
“Therefore, the pronounced upregulation of S100A8/A9 in ADAP-deficient colitis mice likely reflects aggravated intestinal inflammation”
Quote in the paperSubstantial claim - Premisecitation
S100A8/A9 expression positively correlates with disease severity.
“their expression positively correlates with disease severity [24].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Shiotani, A., H. Kusunoki, Y. Kimura, M. Ishii, H. Imamura, K. Tarumi, et al. 2013. S100A expression and interleukin-10 polymorphisms are associated with ulcerative colitis and diarrhea predominant irritable bowel syndrome. Digestive Diseases and Sciences 58 (8): 2314–2323. source
- Interpretationown data
ADAP deficiency in macrophages exacerbates colitis by dysregulating the S100A8/A9-NF-κB axis.
“These results demonstrate that ADAP deficiency in macrophages exacerbates colitis by dysregulating the S100A8/A9-NF-κB axis, establishing a crucial mechanistic connection between ADAP and inflammatory signaling in the gut.”
Quote in the paperSubstantial claim - Interpretationreasoning
ADAP deficiency increases SPI1 expression for transcription of the S100A8/A9 promoter.
“ADAP deficiency increases SPI1 expression for transcription of the S100A8/A9 promoter.”
Quote in the paperSubstantial claim - Interpretationreasoning
ADAP plays a potential regulatory role in maintaining intestinal immune balance.
“further supporting a potential regulatory role of ADAP in maintaining intestinal immune balance.”
Quote in the paperSubstantial claim - Interpretationown data
ADAP deficiency increases susceptibility to DSS-induced colitis due to upregulation of S100A8/A9 expression.
“This study reveals that ADAP-deficient mice have increased susceptibility to dextran sulfate sodium (DSS)-induced colitis and intestinal inflammation due to upregulation of S100A8/A9 expression (also known as MRP8 and MRP14, respectively) both in vivo and in vitro.”
Quote in the paperSubstantial claim - Interpretationown data
ADAP plays a protective role in mitigating intestinal inflammation in experimental colitis.
“Taken together, these results indicate that ADAP plays a protective role in mitigating intestinal inflammation, highlighting it as a key regulator of the immune response in experimental colitis.”
Quote in the paperSubstantial claim - Interpretationown data
Macrophages are critical mediators of ADAP-dependent regulation of colonic inflammation.
“Altogether, these findings demonstrate that macrophages are critical mediators of ADAP-dependent regulation of colonic inflammation, highlighting their pivotal role in ADAP’s anti-inflammatory function during colitis.”
- Also stated in: § The Presence of Colonic Macrophages Aggravates Colitis in ADAP-deficient Mice · hedged
“These findings indicate that ADAP primarily regulates colitis through immune cells, particularly macrophages.”
Quote in the paperSubstantial claim - Also stated in: § The Presence of Colonic Macrophages Aggravates Colitis in ADAP-deficient Mice · hedged
- Interpretationown data
FBXW7 is a critical post-translational regulator of SPI1 stability.
“These findings establish FBXW7 as a critical post-translational regulator of SPI1 stability and link its dysregulation to the hyperinflammatory phenotype in ADAP-knockdown macrophages.”
Quote in the paperSubstantial claim - Interpretationown data
K48-linked polyubiquitination drives SPI1 proteasomal degradation.
“Mutagenesis analysis revealed that K48, but not K63, served as the primary ubiquitination site, indicating that K48-linked polyubiquitination drives SPI1 proteasomal degradation (Fig. 8D).”
Quote in the paperSubstantial claim - Interpretationown data
ADAP promotes proteasomal degradation of SPI1 via the E3 ubiquitin ligase FBXW7-mediated ubiquitination.
“Mechanistically, ADAP promotes proteasomal degradation of the transcription factor SPI1 (SPI-1 proto-oncogene) via the E3 ubiquitin ligase FBXW7 (F-box and WD repeat domain-containing 7)-mediated ubiquitination.”
Quote in the paperSubstantial claim - Interpretationown data
The exacerbation of DSS-induced colonic inflammation in ADAP deficiency appears closely associated with macrophages.
“This exacerbation appears to be closely associated with macrophages, as our preliminary data demonstrated that ADAP-deficient macrophages preferentially polarize toward the pro-inflammatory M1 phenotype”
Quote in the paperSubstantial claim - Interpretationown data
ADAP-deficient macrophage M1 polarization may contribute to enhanced inflammatory progression.
“which may contribute to enhanced inflammatory progression [15].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Yang, N., Y. Xiong, Y. Wang, Y. Yi, J. Zhu, F. Ma, et al. 2021. ADAP Y571 phosphorylation is required to prime STAT3 for activation in TLR4-stimulated macrophages. The Journal of Immunology 206 (4): 814–826. source
- Interpretationreasoning
ADAP suppresses the expression of downstream effectors S100A8 and S100A9.
“In inflammatory macrophages, ADAP upregulates FBXW7 expression and promotes ubiquitin-proteasome-mediated degradation of the transcription factor SPI1, thereby suppressing the expression of downstream effectors S100A8 and S100A9.”
Quote in the paperSubstantial claim - Interpretationreasoning
The ADAP-FBXW7-SPI1-S100A8/A9 axis may serve as a potential therapeutic target for inflammatory bowel disease.
“suggest that the ADAP–FBXW7–SPI1–S100A8/A9 axis may serve as a potential therapeutic target for inflammatory bowel disease.”
Quote in the paperSubstantial claim- Rests on an assumption: The DSS-induced acute colitis mouse model is a valid model for human inflammatory bowel disease.
- Interpretationown data
ADAP regulates macrophage-mediated inflammatory responses via the FBXW7-SPI1-S100A8/A9 signaling axis.
“It regulates macrophage-mediated inflammatory responses via the FBXW7–SPI1–S100A8/A9 signaling axis, thereby contributing to intestinal immune homeostasis (Fig. 9).”
Quote in the paperSubstantial claim - Interpretationown data
ADAP plays an important role in limiting intestinal inflammation.
“We demonstrate that ADAP, a key immunomodulatory protein, plays an important role in limiting intestinal inflammation.”
Quote in the paperSubstantial claim - Interpretationreasoning
ADAP contributes to intestinal immune homeostasis.
“It regulates macrophage-mediated inflammatory responses via the FBXW7–SPI1–S100A8/A9 signaling axis, thereby contributing to intestinal immune homeostasis (Fig. 9).”
Quote in the paperSubstantial claim - Interpretationreasoning
ADAP exerts anti-inflammatory effects through transcriptional repression.
“Specifically, ADAP exerts anti-inflammatory effects through transcriptional repression.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 21
- May combine two claims. 17
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationS100A8/A9 is recognized as both a biomarker of colitis and a promoter of inflammation-associated tumorigenesis.
“Importantly, S100A8/A9 has been recognized as both a biomarker of colitis and a promoter of inflammation-associated tumorigenesis [16–18].”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [16] Wang, S., R. Song, Z. Wang, Z. Jing, S. Wang, and J. Ma. 2018. S100A8/A9 in inflammation. Frontiers in Immunology 9: 1298. source
- cites [17] Kessel, C., M. Lavric, T. Weinhage, M. Brueckner, S. de Roock, J. Däbritz, et al. 2021. Serum biomarkers confirming stable remission in inflammatory bowel disease. Scientific Reports 11 (1): 6690. source
The Results (page unavailable) identify S100A8/A9 as a marker distinguishing ulcerative colitis patients with future flares from those with stable remission, supporting its biomarker role in that setting. The paper does not address whether S100A8/A9 promotes inflammation-associated tumorigenesis. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [18] Reichman, H., I. Moshkovits, M. Itan, M. Pasmanik-Chor, T. Vogl, J. Roth, et al. 2017. Transcriptome profiling of mouse colonic eosinophils reveals a key role for eosinophils in the induction of s100a8 and s100a9 in mucosal healing. Scientific Reports 7 (1): 7117. source
The Results and Discussion report increased S100A8/A9 expression during experimental colitis, including in colonic biopsies and serum, which supports its association with colitis but does not establish it as a validated biomarker. The Discussion links S100A8/A9 to cancer and says these proteins can facilitate cancer-cell migration; it does not establish that they promote inflammation-associated tumorigenesis. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationS100A8/A9 is predominantly secreted by monocytes, macrophages, and neutrophils, serving as a key amplifier of inflammatory responses.
“It is predominantly secreted by monocytes, macrophages, and neutrophils, serving as a key amplifier of inflammatory responses [16].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Wang, S., R. Song, Z. Wang, Z. Jing, S. Wang, and J. Ma. 2018. S100A8/A9 in inflammation. Frontiers in Immunology 9: 1298. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationConcurrent deficiency of ADAP and SKAP55 suppresses PD-1 expression in CD8+ T cells.
“concurrent deficiency of ADAP and SKAP55 suppresses PD-1 expression in CD8⁺ T cells, thereby enhancing anti-tumor immunity [21].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] Li, C., W. Li, J. Xiao, S. Jiao, F. Teng, S. Xue, et al. 2015. ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8 + cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy. EMBO Molecular Medicine 7 (6): 754–769. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationS100A8/A9 potentiates NF-κB signaling activation.
“Moreover, S100A8/A9 has been shown to potentiate NF-κB signaling activation [16].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Wang, S., R. Song, Z. Wang, Z. Jing, S. Wang, and J. Ma. 2018. S100A8/A9 in inflammation. Frontiers in Immunology 9: 1298. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationADAP modulates macrophage polarization and phagocytic capacity through direct interactions with STAT3 and STAT1.
“Furthermore, ADAP modulates macrophage polarization and phagocytic capacity through direct interactions with the STAT family members STAT3 and STAT1 [14, 15].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [14] Xiong, Y., Y. Li, X. Cui, L. Zhang, X. Yang, and H. Liu. 2022. ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia. Cellular & Molecular Immunology 19 (8): 898–912. source
- cites [15] Yang, N., Y. Xiong, Y. Wang, Y. Yi, J. Zhu, F. Ma, et al. 2021. ADAP Y571 phosphorylation is required to prime STAT3 for activation in TLR4-stimulated macrophages. The Journal of Immunology 206 (4): 814–826. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSPI1 is essential for the differentiation and function of lymphoid and myeloid cells.
“the transcription factor SPI1—essential for the differentiation and function of lymphoid and myeloid cells [25]—has also been implicated in inflammatory regulation.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [25] Huang, J., W. Chen, Z. Jie, and M. Jiang. 2022. Comprehensive analysis of immune implications and prognostic value of SPI1 in gastric cancer. Frontiers in Oncology 12: 820568. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn Alzheimer's disease, SPI1 overexpression increases disease risk.
“In Alzheimer’s disease, SPI1 downregulation confers protection, whereas its overexpression increases disease risk [26].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] Pimenova, A.A., M. Herbinet, I. Gupta, S.I. Machlovi, K.R. Bowles, E. Marcora, et al. 2021. Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response. Neurobiology of Disease 148: 105217. source
The Introduction states that increased SPI1/PU.1 expression is associated with higher Alzheimer’s disease risk, while reduced expression confers protection. The paper does not establish that experimentally overexpressing SPI1 increases disease risk; its overexpression experiments were conducted in cultured microglial cells. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationS100A8/A9 is a marker of intestinal inflammation to predict the degree of inflammatory response.
“S100A8/A9 has been recognized as a marker of intestinal inflammation to predict the degree of inflammatory response [8, 9].”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [8] Li, J., and A.M. Schmidt. 1997. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. Journal of Biological Chemistry 272 (26): 16498–16506. source
The Discussion links LPS-responsive RAGE expression to an inflammatory response, but does not discuss S100A8/A9 as a marker of intestinal inflammation or as a predictor of its degree. Searches for S100A8/A9 and calprotectin did not locate a passage addressing that claim in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [9] Eggers, K., K. Sikora, M. Lorenz, T. Taubert, M. Moobed, G. Baumann, et al. 2011. RAGE-dependent regulation of calcium-binding proteins S100A8 and S100A9 in human THP-1. Experimental and Clinical Endocrinology & Diabetes 119 (6): 353–357. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationConcurrent deficiency of ADAP and SKAP55 enhances anti-tumor immunity.
“concurrent deficiency of ADAP and SKAP55 suppresses PD-1 expression in CD8⁺ T cells, thereby enhancing anti-tumor immunity [21].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] Li, C., W. Li, J. Xiao, S. Jiao, F. Teng, S. Xue, et al. 2015. ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8 + cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy. EMBO Molecular Medicine 7 (6): 754–769. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn macrophages, ADAP orchestrates integrin signaling and actin remodeling via the ADAP/SKAP2/Sirpα complex.
“In macrophages, ADAP orchestrates integrin signaling (both inside-out and outside-in) and actin remodeling via the ADAP/SKAP2/Sirpα complex [13].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Alenghat, F.J., Q.J. Baca, N.T. Rubin, L.I. Pao, T. Matozaki, C.A. Lowell, et al. 2012. Macrophages require Skap2 and Sirpα for integrin-stimulated cytoskeletal rearrangement. Journal of Cell Science 125 (Pt 22): 5535–5545. source
The Discussion proposes that a Sirpα/Skap2/Adap complex links outside-in integrin signaling to actin remodeling in macrophages. It does not establish that ADAP orchestrates both directions of signaling: the Discussion says defects in inside-out signaling are unlikely to explain the impaired actin ruffling, and identifies Skap2 as a key mediator. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn sepsis, ADAP alleviates systemic inflammation by reshaping macrophage function through TLR4-induced PDPN expression.
“In sepsis, ADAP alleviates systemic inflammation by reshaping macrophage function through TLR4-induced PDPN expression [19].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Zhang, P., X. Wang, X. Yang, and H. Liu. 2025. Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis. JCI Insight 10(6): e186486. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn Alzheimer's disease, SPI1 downregulation confers protection.
“In Alzheimer’s disease, SPI1 downregulation confers protection, whereas its overexpression increases disease risk [26].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [26] Pimenova, A.A., M. Herbinet, I. Gupta, S.I. Machlovi, K.R. Bowles, E. Marcora, et al. 2021. Alzheimer’s-associated PU.1 expression levels regulate microglial inflammatory response. Neurobiology of Disease 148: 105217. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn immune thrombocytopenia, ADAP inhibits STAT1 signaling to regulate macrophage phagocytosis.
“in immune thrombocytopenia, we demonstrated that ADAP inhibits STAT1 signaling to regulate macrophage phagocytosis [14].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Xiong, Y., Y. Li, X. Cui, L. Zhang, X. Yang, and H. Liu. 2022. ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia. Cellular & Molecular Immunology 19 (8): 898–912. source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDuring viral VSV infection, ADAP interacts with RIG-I to modulate type I interferon responses in macrophages.
“During viral VSV infection, ADAP interacts with RIG-I to modulate type I interferon responses in macrophages [20].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [20] Wang, Y., H. Feng, X. Li, Y. Ruan, Y. Guo, X. Cui, et al. 2024. Dampening of isgylation of RIG-I by ADAP regulates type I interferon response of macrophages to RNA virus infection. PLoS Pathogens 20 (5): e1012230. source
The Discussion reports that ADAP deficiency reduces type I interferon production in macrophages after VSV infection and that ADAP interacts with RIG-I during RNA-virus infection. The Results section on ADAP–RIG-I interaction tests that interaction during SeV infection, not specifically during VSV infection, so the VSV-specific interaction is not established by our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationADAP deficiency skews macrophages toward a pro-inflammatory M1 phenotype, amplifying production of inflammatory cytokines.
“Our prior work firmly established that ADAP deficiency skews macrophages toward a pro-inflammatory M1 phenotype, amplifying their production of inflammatory cytokines [14, 15].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [14] Xiong, Y., Y. Li, X. Cui, L. Zhang, X. Yang, and H. Liu. 2022. ADAP restraint of STAT1 signaling regulates macrophage phagocytosis in immune thrombocytopenia. Cellular & Molecular Immunology 19 (8): 898–912. source
The Results section reports enriched proinflammatory signaling pathways in Adap−/− splenic macrophages, and the Discussion says this suggests a shift toward a proinflammatory phenotype. The cited passages do not establish an M1 phenotype or show increased inflammatory cytokine production; pathway enrichment is not a measurement of cytokine output. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [15] Yang, N., Y. Xiong, Y. Wang, Y. Yi, J. Zhu, F. Ma, et al. 2021. ADAP Y571 phosphorylation is required to prime STAT3 for activation in TLR4-stimulated macrophages. The Journal of Immunology 206 (4): 814–826. source
May combine two claims.
Findingown dataADAP expression is elevated in colonic tissues from patients with ulcerative colitis and in mice with DSS-induced acute colitis.
“Supporting this notion, our re-analysis of public transcriptomic data revealed elevated ADAP expression in colonic tissues from patients with ulcerative colitis and in mice with DSS-induced colitis (Fig. 1A-B).”
- Also stated in: § ADAP Expression is Upregulated in Ulcerative and Dss-induced Colitis · plain
“Consistent with the bioinformatics analysis, ADAP expression was markedly increased at both the protein and mRNA levels in colonic tissues from DSS-treated mice, as determined by western blotting and RT-qPCR (Fig. 1E).”
- Also stated in: § ADAP Expression is Upregulated in Ulcerative and Dss-induced Colitis · boosted
“Collectively, these results demonstrate that ADAP expression is elevated in both ulcerative colitis and DSS-induced acute colitis.”
Quote in the paperSubstantial claim- Also stated in: § ADAP Expression is Upregulated in Ulcerative and Dss-induced Colitis · plain
May combine two claims.
Findingown dataDSS-treated ADAP-deficient mice exhibit 1,041 differentially expressed genes relative to WT, with 699 upregulated and 342 downregulated genes.
“Specifically, DSS-treated ADAP-deficient mice exhibited 1,041 differentially expressed genes (DEGs) relative to their WT counterparts, with 699 upregulated and 342 downregulated genes(Fig. 5A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataADAP deficiency increases SPI1 protein levels without affecting Spi1 mRNA expression in vivo and in vitro.
“Both in vivo ADAP deletion and in vitro ADAP knockdown markedly increased SPI1 protein levels without affecting Spi1 mRNA expression (Fig. 7C-F), suggesting post-transcriptional regulation.”
Quote in the paperSubstantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataSPI1 binds to the S100A8/A9 promoter and mediates its transcriptional activation.
“Further analysis with the JASPAR database identified SPI1-binding motifs within the S100A8/A9 promoter region (Fig. 7A).”
- Also stated in: § ADAP Modulates S100A8/A9 Expression Through SPI1-dependent Transcription · boosted
“Subsequent CUT&RUN analysis confirmed that ADAP deficiency promoted SPI1-mediated transcriptional activation in RAW264.7 cells. This led to elevated S100A8/A9 expression (Fig. 7B).”
Quote in the paperSubstantial claim- Also stated in: § ADAP Modulates S100A8/A9 Expression Through SPI1-dependent Transcription · boosted
May combine two claims.
Findingown dataADAP-deficient mice exhibit increased susceptibility to DSS-induced colitis, with greater disease severity than WT controls.
“ADAP-deficient mice exhibited significantly greater disease severity compared to WT controls (Fig. 2A).”
- Also stated in: § ADAP Deficiency Exacerbates DSS-induced Colitis and Amplifies the Inflammatory Response · plain
“This was evident as increased body weight loss (Fig. 2B), more pronounced colon shortening (Fig. 2C), higher pathological scores, and greater damage to the colonic mucosa (Fig. 2D).”
Quote in the paperSubstantial claim- Also stated in: § ADAP Deficiency Exacerbates DSS-induced Colitis and Amplifies the Inflammatory Response · plain
May combine two claims.
Findingown dataUpon LPS stimulation, FBXW7 expression increased in WT macrophages, whereas USP7 expression remained unchanged.
“Upon LPS stimulation, FBXW7 expression increased in WT macrophages, whereas USP7 remained unchanged.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataADAP deficiency leads to enhanced expression of S100A8/A9 and activation of the NF-κB pathway in colonic tissues.
“To validate these transcriptomic findings, we confirmed at the protein level that ADAP deficiency led to enhanced expression of S100A8/A9 and activation of the NF-κB pathway in colonic tissues (Fig. 6A).”
- Also stated in: § ADAP Deficiency in Macrophages Drives NF-κB-dependent Transcriptional Activation of S100A8/A9 · boosted
“Consistently, RT-qPCR and ELISA analyses demonstrated significantly elevated levels of S100A8/A9 in ADAP-deficient mice with acute colitis (Fig. 6B-C), corroborating the RNA-seq results.”
Quote in the paperSubstantial claim- Also stated in: § ADAP Deficiency in Macrophages Drives NF-κB-dependent Transcriptional Activation of S100A8/A9 · boosted
May combine two claims.
Interpretationown dataThe ADAP-SPI1-S100A8/A9 axis is a critical pathway driving macrophage-mediated inflammation and exacerbating colitis in ADAP-deficient mice.
“These findings reveal the ADAP–SPI1–S100A8/A9 axis as a critical pathway driving macrophage-mediated inflammation and exacerbating colitis in ADAP-deficient mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationS100A8/A9 serves as a reliable biomarker and potential therapeutic target for intestinal inflammation.
“among which S100A8/A9 serves as both a reliable biomarker and a potential therapeutic target for intestinal inflammation [11, 22].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11] Liu, C., Y.X. He, J.N. Zhang, F. Yang, S.Y. Wang, J.L. Hu, et al. 2023. Angelica oil restores the intestinal barrier function by suppressing S100A8/A9 signalling in mice with ulcerative colitis. Phytomedicine 108: 154490. source
- cites [22] Manolakis, A.C., A.N. Kapsoritakis, E.K. Tiaka, and S.P. Potamianos. 2011. Calprotectin, calgranulin C, and other members of the s100 protein family in inflammatory bowel disease. Digestive Diseases and Sciences 56 (6): 1601–1611. source
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenADAP has been implicated in diverse immune-related processes in a cell type- and context-dependent manner.
“Consistent with these findings, ADAP has been implicated in diverse immune-related processes in a cell type- and context-dependent manner.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataADAP deficiency promotes SPI1-dependent transcriptional activation of S100A8/A9, resulting in enhanced NF-κB signaling.
“Taken together, these in vivo and in vitro results demonstrate that ADAP deficiency promotes SPI1-dependent transcriptional activation of S100A8/A9, resulting in enhanced NF-κB signaling.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationADAP is a hematopoietic cell-specific immune adaptor protein encoded by the Fyb gene.
“Notably, adhesion and degranulation protein (ADAP), also known as FYB, is a hematopoietic cell-specific immune adaptor protein encoded by the Fyb gene [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] Jung, S.H., E.H. Yoo, M.J. Yu, H.M. Song, H.Y. Kang, J.Y. Cho, et al. 2016. ARAP, a novel adaptor protein, is required for TCR signaling and integrin-mediated adhesion. The Journal of Immunology 197 (3): 942–952. source
Classified as probably not a substantial claim.
PremisecitationSPI1 has been implicated in inflammatory regulation.
“the transcription factor SPI1—essential for the differentiation and function of lymphoid and myeloid cells [25]—has also been implicated in inflammatory regulation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductnone givenAfter co-housing, mice were randomly assigned to control or DSS groups.
“After co-housing, mice were separated into genotype-specific cages and randomly assigned to control or DSS groups.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningThe observed colitis phenotype in global ADAP knockout mice might also reflect contributions from non-myeloid cells lacking ADAP.
“Therefore, the observed colitis phenotype might also reflect contributions from non-myeloid cells lacking ADAP.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningAberrant overproduction of S100A8/A9 triggers excessive inflammatory responses and exacerbates DSS-induced colitis.
“ADAP deficiency disrupts this checkpoint, leading to SPI1 accumulation and aberrant overproduction of S100A8/A9, which triggers excessive inflammatory responses and exacerbates DSS-induced colitis”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataADAP deficiency disrupts this checkpoint, leading to SPI1 accumulation and aberrant overproduction of S100A8/A9.
“ADAP deficiency disrupts this checkpoint, leading to SPI1 accumulation and aberrant overproduction of S100A8/A9, which triggers excessive inflammatory responses and exacerbates DSS-induced colitis”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn inflammatory macrophages, ADAP upregulates FBXW7 expression and promotes ubiquitin-proteasome-mediated degradation of SPI1.
“In inflammatory macrophages, ADAP upregulates FBXW7 expression and promotes ubiquitin-proteasome-mediated degradation of the transcription factor SPI1, thereby suppressing the expression of downstream effectors S100A8 and S100A9.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductreasoningWT and ADAP-deficient mice were co-housed for 2 weeks prior to DSS administration to minimize variations in gut microbiota.
“To minimize variations in gut microbiota, WT and ADAP-deficient mice were co-housed in the same cage (6–8 mice per cage) for 2 weeks prior to DSS administration to standardize microbial composition via coprophagy and environmental exposure.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The upstream regulators of S100A8/A9 expression in intestinal macrophages are poorly defined.
“While targeting S100A8/A9 holds therapeutic promise, the upstream regulators that dictate its expression in intestinal macrophages remain poorly defined.”
The paper relies on this without support.
The role of ADAP in modulating S100A8/A9 and in intestinal macrophage function remains unclear.
“As a key regulator of macrophage inflammatory responses, it may be involved in this regulatory network, yet its role in modulating S100A8/A9 or intestinal macrophage function remains unclear.”
“Although the immune adaptor protein ADAP plays a critical role in regulating the inflammatory responses of macrophages, its impact on the function of intestinal macrophages in intestinal immunity remains elusive.”
The paper relies on this without support.
The DSS-induced acute colitis mouse model is a valid model for human inflammatory bowel disease.
“we established a DSS-induced acute colitis mouse model”
“potential therapeutic target for inflammatory bowel disease”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Macrophage-depletion injection schedule differs between figure and methods
MajorFigure 4 places the first clodronate injection one day before DSS treatment, whereas the methods place it on DSS treatment day 1.
“Mice were intraperitoneally injected with 200 µL clodronate liposomes (macrophage depletion) one day before DSS treatment, two days after initiation, and on day 5 of DSS administration”
“To deplete macrophages, each mouse received 200 µL of clodronate liposomes (Yeasen, 40337ES08, China) via intraperitoneal injection on DSS treatment days 1, 2, and 5.”
Figure captions and methods disagree on whether error bars show SD or SEM
MinorThe figure captions state that data are presented as mean ± SD, while the Statistical Analysis section says all data are presented as means ± SEM. These are different measures of variability.
“Data are presented as mean ± SD from at least three independent experiments.”
“All data were analyzed using GraphPad Prism 8 and are presented as means ± SEM.”
Figure 4E is described as systemic cytokine data but measures colonic tissue
MinorThe results text cites Figure 4E as evidence of changes in systemic inflammatory cytokine levels. Its caption instead describes RT-qPCR measurements in colonic tissues.
“systemic inflammatory cytokine levels (Fig. 4E)”
“E RT-qPCR analysis of proinflammatory cytokines (Tnfα, Il6, Il1β) in colonic tissues.”
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Flagged first, then by citations
- Authors
- Wang, Y., Li, X., Lv, X., Zhang, P., & Liu, H.
- Affiliations
- Soochow University (CN)
- Corresponding author
- Liu, Hebin
- Venue
- Inflammation
- Published
- 2026-01-06
- Volume
- 49
- Issue
- 1
- Pages
- 27-27
- ISSN
- 0360-3997 (ISSN-L)
- 1573-2576
- PMC
- PMC12831714
- OpenAlex
- W7119171670
- Cited by
- 0
- References
- 28
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Inflammation (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Natural Science Foundation of Jiangsu Higher Education Institution-Key Program (21KJA310002)
- National Natural Science Foundation of China (31470840)
- Soochow University Research Development Funds (Q424900220,)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- ADAP, PU.1, S100A8/A9, colitis, intestinal inflammation, macrophages, FBXW7, ubiquitination
- MeSH terms
- Proto-Oncogene Mas, Animals, Colitis, Humans, Macrophages, Mice, Inbred C57BL
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