Complement genes expression by human keratinocytes and their modulation by a necrotizing venom

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Keratinocytes are important components of the skin immune system. They are able to produce several mediators, including cytokines, chemokines and complement proteins. So far, it has been reported that keratinocytes produce complement components C1q, C1r, C1s, C2, C3, C4, C5, C7, C8 g, C9, FB; complement receptors CR1, cC1qR, C5aR, CR2; soluble complement regulators FP, C1-INH, FH and cell surface complement regulatory proteins DAF, CD59 and MCP. Toxins found in animal venoms have been shown to interact with the human C-system and, in many cases, C-activation may contribute to venom induced pathology. We have shown that the brown recluse (Loxosceles) spider bite promotes dermonecrosis. Its venom induces activation of cell surface metalloproteases able to cleave MCP (CD46) on human keratinocytes, although no increase in Complement susceptibility was observed. Thus, in order to further investigate the action of Loxosceles venom on human keratinocytes (HaCat cells), analysis of the repertoire of expressed genes was performed by RNA-seq. Transcriptomes of keratinocytes cell cultures, treated with PBS or Loxosceles venom, were sequenced and mapped against human genome. Differentially expressed genes (DEG) were calculated using edgeR R-package. The expression of C-components C1q, C1r, C1s, C2, C3, C4, C5, C9, FB, FH, MCP and C5aR1 was identified in control HaCat cells and their expression was not modulated by venom. Furthermore, the expression of MASP2, FD, CR3 (CD11b/CD18) and Clusterin in human keratinocytes is here described for the first time and their expression was not modulated by venom. Bioinformatics’ analyses showed three up-regulated complement DEGs (DAF, CD59 and FP) and only one down-regulated (C8γ) in venom-treated cells. It was also shown upstream up-regulation of the Heparin Binding EGF-Like Growth Factor (HB-EGF) associated with DAF up-regulation, possibly via Blc-6. HB-EGF plays a pivotal role in wound repair, inducing the migration and proliferation of keratinocytes. These data suggest that keratinocytes are fully able to produce C-components involved in the activation and regulation of this system. Moreover, the increase in DAF and CD59 genes expression may counterbalance the MCP cell surface cleavage, induced by the spider venom, reinforcing keratinocytes’ cytoprotection against C-attack.
Lopes PH, Ching ATC, Martins Junior J, Lichtenstein F, Trufen C, Chudzinski-Tavassi AM, et al. Complement genes expression by human keratinocytes and their modulation by a necrotizing venom. Mol. Immunol. 2018 Oct;102:217. doi:10.1016/j.molimm.2018.06.221.
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