Formyl Peptide Receptors and Annexin A1: Complementary Mechanisms to Infliximab in Murine Experimental Colitis and Crohn’s Disease

Paula-Silva, Marina de; Rocha, Gustavo Henrique Oliveira da; Broering, Milena Fronza; Queiroz, Maria Luiza; Sandri, Silvana; Loiola, Rodrigo Azevedo; Oliani, Sônia Maria; Vieira, Andréa; Perretti, Mauro; Farsky, Sandra Helena Poliselli

doi:10.3389/fimmu.2021.714138

Cited by 10 publications

(6 citation statements)

References 43 publications

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“… 48 The oral administration of DSS triggers the peak of the disease on Day 6, and the withdrawal of DSS promotes the initial recovery of tissue on Day 10. 16 , 22 , 29 , 49 Hence, oral Eudragit-SBA-15-Ac2-26 treatment started at the peak of the disease (Day 6) and was maintained at the beginning of the recovery phase (Day 10). Treatments were performed once a day based on the TGI distribution of SBA-15 and peptide release.…”

Section: Resultsmentioning

confidence: 99%

“… 25 , 26 Moreover, AnxA1 is highly expressed by neutrophils and macrophages in the lamina propria and mediates efferocytosis via FPR2 agonism. 16 , 22 Ac2-26 acts similar to AnxA1, binding to both receptors for downstream anti-inflammatory and tissue repair through intracellular pathways and impairing the migration of macrophages and neutrophil to the site of the inflammation. 65 These concepts can be applied to SBA-15 distribution and the biological response of Ac2-26 to oral treatment of colitis.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15][16][17] Interactions between AnxA1 and FPR1 mediate IBD wound closure, and FPR2 promotes mucosal healing by regulating the trafficking and functions of leukocytes into inflamed tissue. [18][19][20][21][22] Ac2-26 comprises 25 amino acids of the N-terminal sequence of AnxA1 that bind to FPR1 and 2 to display equivalent biological actions to those of the full-length protein, 8,23,24 including those evoked by AnxA1 on IBD. [25][26][27][28] According to the data, the pharmacological administration of recombinant AnxA1 (rAnxA1) or its synthetic N-terminal-related peptides could play a mandatory role in IBD therapy.…”

Section: Introductionmentioning

confidence: 99%

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Development of Ac2-26 Mesoporous Microparticle System as a Potential Therapeutic Agent for Inflammatory Bowel Diseases

Broering,

Oseliero Filho,

Borges

et al. 2024

IJN

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Inflammatory bowel diseases (IBDs) disrupt the intestinal epithelium, leading to severe chronic inflammation. Current therapies cause adverse effects and are expensive, invasive, and ineffective for most patients. Annexin A1 (AnxA1) is a pivotal endogenous anti-inflammatory and tissue repair protein in IBD. Nanostructured compounds loading AnxA1 or its active N-terminal mimetic peptides improve IBD symptomatology. Methods: To further explore their potential as a therapeutic candidate, the AnxA1 N-terminal mimetic peptide Ac2-26 was incorporated into SBA-15 ordered mesoporous silica and covered with EL30D-55 to deliver it by oral treatment into the inflamed gut. Results:The systems SBA-Ac2-26 developed measurements revealed self-assembled rod-shaped particles, likely on the external surface of SBA-15, and 88% of peptide incorporation. SBA-15 carried the peptide Ac2-26 into cultured Raw 264.7 macrophages and Caco-2 epithelial cells. Moreover, oral administration of Eudragit-SBA-15-Ac2-26 (200 μg; once a day; for 4 days) reduced colitis clinical symptoms, inflammation, and improved epithelium recovery in mice under dextran-sodium sulfate-induced colitis. Discussion: The absorption of SBA-15 in gut epithelial cells is typically low; however, the permeable inflamed barrier can enable microparticles to cross, being phagocyted by macrophages. These findings suggest that Ac2-26 is successfully delivered and binds to its receptors in both epithelial and immune cells, aligning with the clinical results. Conclusion: Our findings demonstrate a simple and cost-effective approach to delivering Ac2-26 orally into the inflamed gut, highlighting its potential as non-invasive IBD therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of Ac2-26 Mesoporous Microparticle System as a Potential Therapeutic Agent for Inflammatory Bowel Diseases

Broering,

Oseliero Filho,

Borges

et al. 2024

IJN

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“…3 K). ANNEXIN inhibits inflammatory responses via formyl peptide receptors (FPRs) [ 29 ]. However, macrophages lacked the annexin-FPR axis signaling pathway (Fig S2F).…”

Section: Resultsmentioning

confidence: 99%

Macrophages as determinants and regulators of systemic sclerosis-related interstitial lung disease

Lee,

Huang,

Oyang

et al. 2024

J Transl Med

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Background Interstitial lung disease (ILD) is the primary cause of mortality in systemic sclerosis (SSc), an autoimmune disease characterized by tissue fibrosis. SSc-related ILD (SSc-ILD) occurs more frequently in females aged 30–55 years, whereas idiopathic pulmonary fibrosis (IPF) is more prevalent in males aged 60–75 years. SSc-ILD occurs earlier than IPF and progresses rapidly. FCN1, FABP4, and SPP1 macrophages are involved in the pathogenesis of lung fibrosis; SPP1 macrophages demonstrate upregulated expression in both SSc-ILD and IPF. To identify the differences between SSc-ILD and IPF using single-cell analysis, clarify their distinct pathogeneses, and propose directions for prevention and treatment. Methods We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databases GSE159354 and GSE212109, and analyzed lung tissue samples across healthy controls, IPF, and SSc-ILD. The primary measures were the filtered genes integrated with batch correction and annotated cell types for distinguishing patients with SSc-ILD from healthy controls. We proposed an SSc-ILD pathogenesis using cell–cell interaction inferences, and predicted transcription factors regulating target genes using SCENIC. Drug target prediction of the TF gene was performed using Drug Bank Online. Results A subset of macrophages activates the MAPK signaling pathway under oxidative stress. Owing to the lack of inhibitory feedback from ANNEXIN and the autoimmune characteristics, this leads to an earlier onset of lung fibrosis compared to IPF. During initial lung injury, fibroblasts begin to activate the IL6 pathway under the influence of SPP1 alveolar macrophages, but IL6 appears unrelated to other inflammatory and immune cells. This may explain why tocilizumab (an anti-IL6-receptor antibody) only preserves lung function in patients with early SSc-ILD. Finally, we identified BCLAF1 and NFE2L2 as influencers of MAPK activation in macrophages. Metformin downregulates NFE2L2 and could serve as a repurposed drug candidate. Conclusions SPP1 alveolar macrophages play a role in the profibrotic activity of IPF and SSc-ILD. However, SSc-ILD is influenced by autoimmunity and oxidative stress, leading to the continuous activation of MAPK in macrophages. This may result in an earlier onset of lung fibrosis than in IPF. Such differences could serve as potential research directions for early prevention and treatment.

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“…Anxa1 is a component of the extracellular vesicles of these immune cells [ 67 ]. When released into the extracellular space, it modifies the inflammatory response of phagocytes and epithelial cells through binding to formyl peptide receptors [ 68 ]. Our included study [ 15 ] found an increased inflammatory score and increased MMP in Anxa1 KO mice, which is consistent with the process described above.…”

Section: Discussionmentioning

confidence: 99%

Knockout Genes in Bowel Anastomoses: A Systematic Review of Literature Outcomes

Geropoulos,

Psarras,

Koimtzis

et al. 2024

JPM

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Background: The intestinal wound healing process is a complex event of three overlapping phases: exudative, proliferative, and remodeling. Although some mechanisms have been extensively described, the intestinal healing process is still not fully understood. There are some similarities but also some differences compared to other tissues. The aim of this systematic review was to summarize all studies with knockout (KO) experimental models in bowel anastomoses, underline any recent knowledge, and clarify further the cellular and molecular mechanisms of the intestinal healing process. A systematic review protocol was performed. Materials and methods: Medline, EMBASE, and Scopus were comprehensively searched. Results: a total of eight studies were included. The silenced genes included interleukin-10, the four-and-one-half LIM domain-containing protein 2 (FHL2), cyclooxygenase-2 (COX-2), annexin A1 (ANXA-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and heparin-binding epidermal growth factor (HB-EGF) gene. Surgically, an end-to-end bowel anastomosis was performed in the majority of the studies. Increased inflammatory cell infiltration in the anastomotic site was found in IL-10-, annexin-A1-, and TAFI-deficient mice compared to controls. COX-1 deficiency showed decreased angiogenesis at the anastomotic site. Administration of prostaglandin E2 in COX-2-deficient mice partially improved anastomotic leak rates, while treatment of ANXA1 KO mice with Ac2-26 nanoparticles reduced colitis activity and increased weight recovery following surgery. Conclusions: our findings provide new insights into improving intestinal wound healing by amplifying the aforementioned genes using appropriate gene therapies. Further research is required to clarify further the cellular and micromolecular mechanisms of intestinal healing.

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Formyl Peptide Receptors and Annexin A1: Complementary Mechanisms to Infliximab in Murine Experimental Colitis and Crohn’s Disease

Cited by 10 publications

References 43 publications

Development of Ac2-26 Mesoporous Microparticle System as a Potential Therapeutic Agent for Inflammatory Bowel Diseases

Development of Ac2-26 Mesoporous Microparticle System as a Potential Therapeutic Agent for Inflammatory Bowel Diseases

Macrophages as determinants and regulators of systemic sclerosis-related interstitial lung disease

Knockout Genes in Bowel Anastomoses: A Systematic Review of Literature Outcomes

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