Inherent differences in keratinocyte function in hidradenitis suppurativa: Evidence for the role of IL-22 in disease pathogenesis

Abstract

Hidradenitis suppurativa (HS) is a chronic, recurrent, inflammatory disease of apocrine gland-bearing skin which affects approximately 1-4% of the population. Defective keratinocyte function has been postulated to play a role in HS pathogenesis. Using an in vitro scratch assay, differences between normal, HS, and chronic wound (CW) keratinocytes were evaluated. Normal keratinocytes exhibited faster scratch closure than HS or CW, with normal samples showing 93.8% closure at 96 hours compared to 80.8% in HS (p = 0.016) and 71.5% in CW (p = 0.0012). The keratinocyte viability was similar in normal and HS (91.12 ± 6.03% and 86.55 ± 3.28%, respectively, p = 0.1583), but reduced in CW (72.34 ± 13.12%, p = 0.0138). Furthermore, apoptosis measured by annexin V/propidium iodide, was higher in CW keratinocytes (32.10 ± 7.29% double negative cells compared to 68.67 ± 10.37% in normal and 55.10 ± 9.46% in HS, p = 0.0075). Normal keratinocytes exhibited a significantly higher level of IL-1α (352.83 ± 42.79 pg/ml) compared to HS (169.96 ± 61.62 pg/ml) and CW (128.23 ± 96.61 pg/ml, p = 0.004). HS keratinocytes exhibited significantly lower amounts of IL-22 (8.01 pg/ml) compared to normal (30.24 ± 10.09 pg/ml) and CW (22.20 ± 4.33 pg/ml, p = 0.0008), suggesting that defects in IL-22 signaling may play a role in HS pathogenesis. These findings support intrinsic differences in keratinocyte function in HS which cannot be attributed to reduced keratinocyte viability or increased apoptosis.

Cytokine Pathways and Investigational Target Therapies in Hidradenitis Suppurativa

“…The lack of IL-22 is associated with insufficient upregulation of AMPs, even in the presence of high levels of IL-17, which results in microbial spread in HS skin [ 103 ]. The decreased expression of IL-22 might be due to reduced infiltration of IL-22-secreting cells and impaired production of IL-22 by these cells [ 89 , 104 ]. IL-22 deficit has also been related to increase of IL-10 production, which might be induced, among others by IL-1β [ 84 ].…”

Hidradenitis suppurativa: A folliculotropic disease of innate immune barrier dysfunction?

“…Keratinocyte function is altered in several other ways in both lesional and perilesional HS skin, including via inflammatory cytokine signalling, wound healing and antimicrobial peptide (AMP) secretion. [53][54][55][56] For instance, keratinocytes from HS lesions secrete excessive levels of the proinflammatory cytokines IL-1β, tumour necrosis factor (TNF)α and IL-23; the latter is speculated to start an autocrine and paracrine inflammatory loop. 57 The targeted ORS keratinocyte population demonstrates increased inflammatory activity in the form of interferon (IFN) release.…”

Hidradenitis suppurativa: infection, autoimmunity, or both?

“…50,65 KCs from HS patients produced less IL-22 compared with those of healthy donors. 45 IL-22 deficiency has also been linked to increased IL-10 production, 65 which might be induced, among others by IL-1β. 65 It is also worth mentioning that IL-22 production is enhanced by Notch signaling, which is defective in some HS patients.…”