Complement C3 Exacerbates Imiquimod-Induced Skin Inflammation and Psoriasiform Dermatitis

Giacomassi, Chiara; Buang, Norzawani; Ling, Guang Sheng; Crawford, Greg; Cook, H. Terence; Scott, Diane; Dazzi, Francesco; Strid, Jessica; Botto, Marina

doi:10.1016/j.jid.2016.11.011

Cited by 20 publications

(22 citation statements)

References 14 publications

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“…[21] The Th17 axis is a known driver of psoriasiform epidermal hyperplasia in human and murine models, and silencing C3 expression in mouse models reduced features of psoriasiform epidermal hyperplasia implying interactions with the Th17 axis. [18] C3 deficient mice were shown to have lower levels of IL-1β, TNFα and IL-17A, as well as decreased skin neutrophil infiltrates [22,23] ; whilst C3astimulated human monocytes induce a strong Th17 response in activated CD4 + T cells. [24] C5aR1 deficient murine models demonstrate impaired IL-23, and Th17 cell differentiation [25] and C5aR1 positive neutrophils and macrophages are present in the inflamed synovium of RA patients.…”

Section: Dys Reg Ul Ati On Of Complement Is a Sso Ciated With Th17 mentioning

confidence: 99%

“…[20] IL-17 administration to mucosal tissue showed a dose-dependent increase in C3 expression, suggesting a self-amplification pathway between Th17 and C3. [28] Superficially, this seems to indicate that complement is significantly implicated in Th17 activation and activity, however, given the role of neutrophil-mediated cytokines and chemokines in mediating Th17 amplification loops, [22][23][24] the possibility that complement levels merely reflect the activity of neutrophils in these disorders needs to be considered. [28] Superficially, this seems to indicate that complement is significantly implicated in Th17 activation and activity, however, given the role of neutrophil-mediated cytokines and chemokines in mediating Th17 amplification loops, [22][23][24] the possibility that complement levels merely reflect the activity of neutrophils in these disorders needs to be considered.…”

Section: Dys Reg Ul Ati On Of Complement Is a Sso Ciated With Th17 mentioning

confidence: 99%

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Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

Grand

Navrazhina

Frew

2019

Experimental Dermatology

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Complement inhibition has been identified as a potential therapeutic target for multiple inflammatory disorders including Hidradenitis Suppurativa (HS). It is currently unclear how complement integrates into our current model of molecular pathogenesis in HS and whether it represents a central component of pathogenesis, or a neutrophil-associated bystander. Levels of C5a in serum and tissue correlate with disease activity and degree of neutrophilic infiltrates in HS. C5a has been associated with Th17 immune axis activation in psoriasis, rheumatoid arthritis and Crohn's disease with strong similarities to TH17 activation in HS. Porphyromonas species (which are identified in the HS microbiome) are able to cleave inactive C5 into C5a implicating the cutaneous microbiome as an activator of complement. C3a and C5a are associated with activation of the NLRP3 inflammasome, implicated in the inflammatory drive in HS. Complement receptors are present upon dendritic cells, monocytes, fibroblasts and adipocytes, which may broaden the potential contribution of complement to multiple aspects of HS pathogenesis. Dysregulation of complement receptor pathways has been documented in obesity, insulin resistance and polycystic ovarian syndrome leading to the possibility that complement may explain the epidemiological associations between these conditions and HS. The therapeutic potential of complement inhibitors in HS may be related to the therapeutic target (complement receptor or complement subunit) and the presence of alternate receptors (such as C5aR2) or ligands (including C3a, PAMPs and DAMPs). Integrating complement into the known pathogenesis of HS may aid in explaining the contradictory results between Phase 2 studies of C5a antagonists. It also allows for the identification of existing knowledge gaps to target further clinical investigation and research.

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Section: Dys Reg Ul Ati On Of Complement Is a Sso Ciated With Th17 mentioning

confidence: 99%

Section: Dys Reg Ul Ati On Of Complement Is a Sso Ciated With Th17 mentioning

confidence: 99%

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

Grand

Navrazhina

Frew

2019

Experimental Dermatology

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“…C3 deficiency also modulates the inflammatory infiltrate of healing by reducing the numbers of neutrophils and increasing the number of mast cells, thus accelerating the whole wound healing process [60]. Additionally, the pro-inflammatory effect of C3 exacerbates the skin inflammation in psoriasiform dermatitis [61].…”

Section: Discussionmentioning

confidence: 99%

Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients’ skin fibroblasts

et al. 2019

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Classical Ehlers-Danlos syndrome (cEDS) is a dominant inherited connective tissue disorder mainly caused by mutations in the COL5A1 and COL5A2 genes encoding type V collagen (COLLV), which is a fibrillar COLL widely distributed in a variety of connective tissues. cEDS patients suffer from skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. Most of the causative variants result in a non-functional COL5A1 allele and COLLV haploinsufficiency, whilst COL5A2 mutations affect its structural integrity. To shed light into disease mechanisms involved in cEDS, we performed gene expression profiling in skin fibroblasts from four patients harboring haploinsufficient and structural mutations in both disease genes. Transcriptome profiling revealed significant changes in the expression levels of different extracellular matrix (ECM)-related genes, such as SPP1, POSTN, EDIL3, IGFBP2, and C3, which encode both matricellular and soluble proteins that are mainly involved in cell proliferation and migration, and cutaneous wound healing. These gene expression changes are consistent with our previous protein findings on in vitro fibroblasts from other cEDS patients, which exhibited reduced migration and poor wound repair owing to COLLV disorganization, altered deposition of fibronectin into ECM, and an abnormal integrin pattern. Microarray analysis also indicated the decreased expression of DNAJB7, VIPAS39, CCPG1, ATG10, SVIP, which encode molecular chaperones facilitating protein folding, enzymes regulating post-Golgi COLLs processing, and proteins acting as cargo receptors required for endoplasmic reticulum (ER) proteostasis and implicated in the autophagy process. Patients’ cells also showed altered mRNA levels of many cell cycle regulating genes including CCNE2, KIF4A, MKI67, DTL, and DDIAS. Protein studies showed that aberrant COLLV expression causes the disassembly of itself and many structural ECM constituents including COLLI, COLLIII, fibronectin, and fibrillins. Our findings provide the first molecular evidence of significant gene expression changes in cEDS skin fibroblasts highlighting that defective ECM remodeling, ER homeostasis and autophagy might play a role in the pathogenesis of this connective tissue disorder.

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“…It was particularly noteworthy that C3e and C5a receptoredeficient mice had accelerated wound healing response time (Rafail et al, 2015). In a murine model of cutaneous inflammation using imiquimod, a toll-like receptor 7/8 antagonist, C3 was found to exacerbate inflammatory response (Giacomassi et al, 2017;. Overall, the levels and impact of complement anaphylatoxins appear to be correlated with the extent of inflammation in these murine models.…”

Section: Complement In Cutaneous Health and Diseasementioning

confidence: 96%

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

Ghias

Hyde

Tomalin

et al. 2020

Journal of Investigative Dermatology

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Although the role of immune dysregulation in hidradenitis suppurativa (HS) has yet to be elucidated, recent studies identified several complement abnormalities in patients with HS. The complement system serves a critical role in the modulation of immune response and regulation of cutaneous commensal bacteria. Complement is implicated in several inflammatory skin diseases including systemic lupus erythematosus, angioedema, pemphigus, bullous pemphigoid, and HS. A model of HS pathogenesis is proposed, integrating the role of commensal bacteria, cutaneous immune responses, and complement dysregulation. The role of complement in disease pathogenesis has led to the development of novel anticomplement agents and clinical trials investigating the efficacy of such treatments in HS.

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Complement C3 Exacerbates Imiquimod-Induced Skin Inflammation and Psoriasiform Dermatitis

Cited by 20 publications

References 14 publications

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

Integrating complement into the molecular pathogenesis of Hidradenitis Suppurativa

Molecular insights in the pathogenesis of classical Ehlers-Danlos syndrome from transcriptome-wide expression profiling of patients’ skin fibroblasts

Role of the Complement Pathway in Inflammatory Skin Diseases: A Focus on Hidradenitis Suppurativa

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