C5a/C5aR1 Pathway Is Critical for the Pathogenesis of Psoriasis

Abstract

Psoriasis is one of the most common chronic inflammatory skin diseases, affecting ~2% of the population. The lack of characterization of the pathogenesis of psoriasis has hindered efficient clinical treatment of the disease. In our study, we observed that expression of complement component 5a receptor 1(C5aR1) was significantly increased in skin lesions of both imiquimod (IMQ) and IL23-induced psoriatic mice and patients with psoriasis. C5aR1 deficiency or treatment with C5a receptor 1 antagonist (C5aR1a) in mice significantly attenuated psoriasis-like skin lesions and expression of inflammatory cytokines and chemokines. Moreover, C5aR1 deficiency significantly decreased IMQ-induced infiltration of plasmacytoid dendritic cells (pDCs), monocytes and neutrophils in psoriatic skin lesions and functions of pDCs, evidenced by the remarkable reduction in the IMQ-induced production of interferon-α (IFN-α) and tumor necrosis factor α (TNF-α), and FMS-like tyrosine kinase 3 ligand (FLT3L)-dependent pDCs differentiation. Accordingly, in vitro treatment with recombinant C5a accelerated pDCs migration and the differentiation of bone marrow cells into pDCs. Furthermore, biopsies of psoriatic patients showed a dramatic increase of C5aR1 + pDCs infiltration in psoriatic skin lesions, compared to healthy subjects. Our results provide direct evidence that C5a/C5aR1 signaling plays a critical role in the pathogenesis of psoriasis. Inhibition of C5a/C5aR1 pathway is expected to be beneficial in the treatment of patients with psoriasis.

Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway

“…Consequently, the potential for aberrant or inadequately regulated complement activity paves the way for disease (7,36,45). As one of the key effector functions, C5ainduced C5aR1 activation, is involved in numerous kidney diseases, but also cardiac remodeling in hypertension (46,47), psoriasis (48), rheumatoid arthritis (49), complications in sepsis (50), neuropathic pain (51), or hidradenitis suppurativa (52). During the recent outbreak of SARS-CoV-2, the potential protective role of C5aR1 blockage in COVID-19-induced cytokine release and endothelial injury is being discussed (17).…”

C5a/C5aR1 mediates IMQ‐induced psoriasiform skin inflammation by promoting IL‐17A production from γδ‐T cells

“…Moreover, we found that C5aR1 was significantly upregulated in both an experimental psoriatic murine model and psoriasis patients 26 . These results clearly suggest that the C5a/C5aR1 pathway promotes psoriasiform dermatitis partly by regulating plasma dendritic cell functions 26 . However, the mechanism underlying the involvement of the C5a/C5aR1 pathway in its pathogenesis remained incompletely understood.…”

“…Male or female mice were treated with daily topical doses (62.5 mg) of commercially available IMQ cream (5%; Si-Chuan Med-Shine Pharmaceutical, H20030128 K E Y W O R D S complement system, C5a, C5aR1, imiquimod, PI3K-Akt signaling, γδ-T cells Chengdu, Sichuan, China) or control cream (Vaseline cream) on the shaved backs or ears of mice for the indicated days. 26 In some experiments, mice were intraperitoneally injected with a C5aR1 antagonist (C5aR1a, peptide sequence: [Ac-Phe-Orn-Pro-dCha-Trp-Arg]; 1 mg/kg; GL Biochem, Shanghai, China) or saline buffer (0.9%) 2 hours before IMQ application. For the IMQ retreatment assays, mice were treated with Vaseline or IMQ cream for 5 days on the shaved back and ear skin.…”

“…Spleens, axillary draining lymphocytes, and skin singlecell suspensions were prepared as previously described. 26,33 Skin samples were minced and digested in collagenase type IV ( anti-mouse CD11b (1 μL/test; CBRM1/5, BioLegend, San Diego, CA, USA), or PE-labeled rat anti-mouse C5aR1 (1 μL/test; 20/70, BioLegend, San Diego, CA, USA) antibodies for 25 minutes on ice in the dark. For IL-17A intracellular staining, the single cell suspension was stimulated with 50 ng/mL of pyromellitic acid, 500 ng/mL of ionomycin (Sigma-Aldrich), and 3 μg/mL of brefeldin A (eBioscience) for 4 hours in 1640 complete medium (RPMI 1640 medium containing 10% fetal calf serum, 100 μg/mL streptomycin, 100 U/mL penicillin, 2 μM glutamine, 50 μM β-mercaptoethanol).…”

“…Disease severity was assessed with an objective scoring system based on the clinical Psoriasis Area and Severity Index (PASI) as previously described. 26,28 Ear skin thickness was tested with a dial thickness gauge (Jiuliang, Shanghai, China). All experiments were blinded for disease induction and experimental read-outs.…”