Limited Presence of IL-22 Binding Protein, a Natural IL-22 Inhibitor, Strengthens Psoriatic Skin Inflammation

Abstract

Psoriasis is a chronic inflammatory disease resulting from dysregulated immune activation associated with a large local secretion of cytokines. Among them, IL-22 largely contributes to epithelial remodeling and inflammation through inhibiting the terminal differentiation of keratinocytes and inducing antimicrobial peptides and selected chemokines. The activity of IL-22 is regulated by IL-22 binding protein (IL-22BP); however, the expression and role of IL-22BP in psoriatic skin has remained unknown so far. Here we showed that nonaffected skin of psoriasis patients displayed lower expression of IL-22BP than skin of healthy controls. Furthermore, the strong IL-22 increase in lesional psoriatic skin was accompanied by a moderate induction of IL-22BP. To investigate the role of IL-22BP in controlling IL-22 during skin inflammation, we used imiquimod-induced skin disease in rodents and showed that rats with genetic IL-22BP deficiency () displayed exacerbated disease that associated with enhanced expression of IL-22-inducible antimicrobial peptides. We further recapitulated these findings in mice injected with an anti-IL-22BP neutralizing Ab. Hypothesizing that the IL-22/IL-22BP expression ratio reflects the level of bioactive IL-22 in psoriasis skin, we found positive correlations with the expression of IL-22-inducible molecules (IL-20, IL-24, IL-36γ, CXCL1, and BD2) in keratinocytes. Finally, we observed that serum IL-22/IL-22BP protein ratio strongly correlated with psoriasis severity. In conclusion, we propose that although IL-22BP can control deleterious actions of IL-22 in the skin, its limited production prevents a sufficient neutralization of IL-22 and contributes to the development and maintenance of epidermal alterations in psoriasis.

Interleukin-22 level is negatively correlated with neutrophil recruitment in the lungs in a Pseudomonas aeruginosa pneumonia model

“…study in which administration of recombinant IL-22BP-Fc resulted in an increase in PMN counts in a cecal legation puncture model of microbial sepsis 40 . More recently, we showed in the imiquimod-induced psoriasis model in mice, known to be IL-22 dependent, that in vivo neutralisation of IL-22BP with the same neutralising antibody used in the present study led to increased severity of psoriasis-like skin inflammation 41 . Taken together, our data highlighted the role of the IL-22/IL-22BP system during bacterial pneumonia and the need for additional studies to assess its therapeutic interest for patients suffering from bacterial pneumonia or ARDS.…”

IL-22: There Is a Gap in Our Knowledge

“…Functional studies using IL-22BP-deficient rodents have shown a protective role for IL-22BP in ischemia reperfusion and acetaminophen-induced liver injury (69). In rats, deficiency of IL-22BP led to exacerbated skin disease in a psoriasis model that was associated with increased IL-22 and antimicrobial peptides (70). IL-22BP has been proposed to have therapeutic potential.…”

Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection

“…47 ] and reduced expression of IL-22BP only exacerbates this process. 48,49 In the intestine, where IL-22 is constitutively expressed to protect the mucosal surface, 50 Il22ra2 −/− mice develop greater number of tumors in a colitis cancer model. 15 Therefore, too much IL-22 can have negative consequences.…”