Aetiology and Pathogenesis of Hidradenitis Suppurativa

K. Wolk; O. Join-Lambert; R. Sabat


The British Journal of Dermatology. 2020;183(6):999-1010. 

In This Article

Role of Specific Cytokines in Hidradenitis Suppurativa

A broad range of immune mediators are highly expressed in established HS lesions compared with healthy control skin.[21,64] Interestingly, most of them are also upregulated in psoriasis,[21,64] which indicates an overlap of certain pathogenetic pathways in both diseases. This supports the clinical investigation of approved antipsoriatic drugs that target respective immune mediators for use in HS. On the other hand, there is a range of cytokines whose levels in HS exceed or are clearly below the levels in psoriasis[21,64] that could point to HS-specific alterations.

Among the mediators known to be mainly produced by macrophages, HS lesional skin shows high levels of the proinflammatory cytokines TNF-α and IL-1β.[21,63,64,85,86] TNF-α mRNA reaches levels similar to those in the inflamed skin of patients with psoriasis,[21,64] a disease that strongly responds to anti-TNF-α therapy.[87] IL-1β upregulation in HS skin greatly exceeds that in psoriatic skin[64] and is not associated with raised levels of the natural IL-1 inhibitor, IL-1 receptor antagonist.[64] The expression of IL-1α, which shares with IL-1β the cellular receptor complex (Figure 4),[88] is also increased in HS lesions compared with healthy donor skin, but this increase is much less pronounced.[64] For secretion of IL-1 protein, the inflammasome system, which represents an integrated PRR/effector system assembling after activation by danger-associated and bacterial molecules, is responsible. HS lesions show increased expression of NLRP3 and P2X7 (the ATP receptor and an inflammasome activator) and increased caspase 1 activity.[63,64,89] Ex vivo analysis of IL-1β protein secretion by different cell populations isolated from lesional HS skin demonstrated macrophages as a major IL-1β source,[64] although lesional keratinocytes were also able to produce this cytokine.[86]

Figure 4.

Cytokines involved in hidradenitis suppurativa (HS) pathogenesis and their receptors. The structures and major downstream signalling factors of the receptor complexes used by cytokines involved in HS pathogenesis are depicted. The expression pattern of the receptor complexes determines the target cells of the cytokines. While some cytokines largely act on both immune and tissue cells [e.g. interleukin (IL)-1β, tumour necrosis factor (TNF)-α and interferon (IFN)-γ], some mainly target immune cells (IL-10) or tissue cells (e.g. IL-22). Therapeutic inhibition of the action of cytokines is possible via neutralization of the cytokines themselves, blocking their specific receptors or interfering with the activation of signalling elements downstream to the receptors. BP, binding protein; Casp., caspases involved in apoptosis; C/EBP, CCAAT-enhancer-binding protein; IRAK, IL-1 receptor-associated kinase; Jak, Janus kinase; MAPK, mitogen-activated protein kinase; NF, nuclear factor; R, receptor; RA, receptor antagonist; RAcP, receptor accessory protein; RBP, RNA-binding protein; Stat, signal transducer and activator of transcription; TRAF, TNF receptor-associated factor; Tyk, tyrosine kinase. [Colour figure can be viewed at]

TNF-α acts on most cells in the body, using two alternative transmembrane receptors (Figure 4) with different biological responses. In the skin, TNF-α induces a wide range of immune-cell-attracting chemokines and contributes to endothelial activation, favouring immune cell infiltration.[90] This function is crucial to each immunological response; it is therefore not surprising that the TNF-α-targeting antibody adalimumab is approved not only for HS[91] but also for psoriasis and psoriasis arthritis, spondyloarthritis and spondyloarthropathy, and Crohn disease.[92–94]

IL-1β also influences every cell type, although, among skin cells, dermal fibroblasts showed the highest IL-1 receptor levels and the strongest IL-1 responses.[6] IL-1β induces the production of MMPs (MMP1, MMP3, MMP10) and various chemokines, with those attracting neutrophilic granulocytes (CXCL1, CXCL6, CXCL8) being most prominent. Moreover, IL-1β induces specific cytokines in its target cells, including IL-6, IL-32 and IL-36β.[64] While the effects of IL-1β on fibroblasts are not clearly shared by other proinflammatory cytokines, in keratinocytes they are often amplified by TNF-α and IL-17. IL-1β target molecules are highly abundant in HS skin.[21,47,64,95,96] The relationship between IL-1β and its target molecules was clearly supported by the reduction of the expression of these target molecules in explanted skin from HS lesions, when treated with an IL-1 receptor antagonist.[64] MMPs may be involved in the early rupture of the hair follicle units and the later loosening of epidermal cell–cell junctions during tunnel formation. Neutrophils attracted by the IL-1-induced chemokines (and maybe by leukotriene B4 and the complement component C5a) contribute to inflammatory cytokine production and pus formation in HS.

Among the cytokines produced by neutrophils in HS (especially after TNF-α stimulation) is lipocalin 2.[97] Apart from its role in inflammatory pain and metabolic control, lipocalin 2 supports further neutrophil tissue infiltration.[98,99] A recent study suggested production of the cathelicidin-derived peptide LL37 by these cells, which the authors claimed to support T-cell proliferation in HS lesions.[47] While little is known about the role of IL-32, IL-6 seems to influence a large range of cells via two alternative signalling ways, involving a membrane-bound and a soluble receptor.[100] In HS lesions, it may, similarly to IL-1β, favour the function of Th17, while impairing the function of regulatory T cells.[101–104] Moreover, IL-6 supports the function of B cells.[100]

Interestingly, in addition to the proinflammatory cytokines, the anti-inflammatory cytokine IL-10 is prominently expressed in HS lesional skin.[21,63,86,105] Macrophages may be the main source of IL-10 in HS. In these cells, IL-10 can be induced by bacterial components and cytokines like TNF-α. Intracellular cAMP levels, induced by nicotine, may further support cutaneous IL-10 production in patients with HS who smoke.[36,37] IL-10 exclusively acts on immune cells via a dimeric receptor complex (Figure 4).[106–108] In myelomonocytic cells, IL-10 strengthens the phagocytosis of bacteria and the clearing away of the apoptotic cells.[109] IL-10 also limits the T-cell stimulation capacity of and proinflammatory cytokine production by monocytes and macrophages.[110–112] Moreover, IL-10 can directly inhibit cytokine production in T cells (see below).[21,113,114]

Among T-cell-typical mediators, the Th17 cell cytokines IL-17A and IL-17F, as well as the Th1 cell cytokine IFN-γ, are highly expressed in HS lesions, with levels comparable with those in psoriasis.[21,64] In contrast, IL-22 shows only limited upregulation.[21] In line with this, HS lesions show an abundance of Th cells able to secrete IL-17 and IFN-γ, but not IL-22·[86] The production of IL-17 and IFN-γ by Th cells (typically Th17 and Th1 cells, respectively) is known to be supported by IL-23, IL-1β and IL-6 (IL-17), as well as by IL-12 (IFN-γ),[75] which are all upregulated in HS lesions.[21] IL-12 and IL-23 were found to be abundantly expressed by macrophages infiltrating the papillary and reticular dermis of lesional skin.[115] Moreover, IL-17 and IFN-γ production is supported by mammalian target of rapamycin (mTOR) complex signalling,[116,117] whose relevance might be deduced from the reported increased mTOR expression in HS lesions.[118]

IL-17A and IL-17F form homo- and heterodimers and share a cellular receptor complex (Figure 4).[119] Their main target cells are epithelial cells, but effects have also been detected on fibroblasts and endothelial cells, for example. IL-17A and IL-17F induce the production of selected chemokines (such as CCL20, attracting Th cell subpopulations and dendritic cells, as well as those specific for neutrophilic granulocytes, such as CXCL1 and CXCL8), cytokines (such as the IL-17 action-enhancing cytokine IL-19) and antimicrobial proteins (AMPs; such as β-defensin-2 and S100A7).[120–124] AMPs are key players in the epidermal immune defence against extracellular bacterial and fungal pathogens. While on their own, IL-17A and IL-17F cause only moderate cell responses, their function lies primarily in the synergistic action with other tissue-active cytokines such as TNF-α, IL-22 and IFN-γ.[123–129] The consequent involvement of IL-17A/F in various cutaneous inflammatory pathways and the high efficacy of approved IL-23 and IL-17 inhibitors in psoriasis led to initiation of clinical studies testing those biologics in HS.[1]

Another Th17 cell cytokine upregulated in HS lesions is IL-26·[21,130] Its biology differs from that of IL-17A/F. While its receptor-dependent cytokine properties are debated, IL-26 directly kills bacteria, an effect that is impaired in HS.[130] Furthermore, IL-26 acts as a carrier of DNA released from damaged cells to intracellular DNA-binding PRRs. The resulting PRR activation, for example in macrophages, induces an inflammatory response.[131]

IFN-γ is a pleiotropic Th/Tc1-cell cytokine that affects both tissue and immune cells via its tetrameric cellular receptor complex (Figure 4).[132] IFN-γ induces chemokines such as CXCR10[133] that attract Th/Tc1 and natural killer cells and that are also upregulated in the skin of patients with HS.[85,134] Moreover, IFN-γ supports the activation of dermal endothelia.[132] It also strengthens proinflammatory cytokine production by macrophages and regulates B-cell functions. On both tissue and antigen-presenting immune cells, it upregulates the surface expression of the major histocompatibility complex and costimulatory molecules, which may be important for local T-cell activation in HS.[132]

The limited upregulation of IL-22 in HS lesions is due to both the limited increase in the frequency of IL-22-producing Th cells, as reported by Hotz et al. (see above),[86] and the inhibited production of this cytokine by Th cells. Regarding the latter, IL-10 might be involved, as deduced from the inhibitory effect of IL-10 on IL-22 production in vitro and the negative correlation between lesional levels of IL-22 and IL-10 in HS.[21] Not only the production but also the impact of IL-22 may be limited in HS. This was concluded from the increased expression of IL-22-binding protein,[21] the natural soluble receptor that inhibits the cutaneous action of IL-22·[135,136] In the skin, IL-22 acts exclusively on keratinocytes.[137,138] Like IL-17, IL-22 is an inducer of epidermal AMPs.[137] It does so both directly and via the induction of IL-20, its downstream mediator, which shares with IL-22 a receptor complex subunit (IL-22R1) (Figure 4).[21,129,137]

Regarding AMP induction, IL-22 acts with IL-17 in a synergistic manner, and only the strong presence of both cytokines results in strong AMP upregulation, which is essential for the protection of disturbed skin.[21,124,137] Consequently, the relative IL-22 deficiency in HS lesions leads to minimal AMP upregulation.[21,96] This may explain the abnormal bacterial colonization of HS lesions and the elevated frequency of skin infections in respective patients.[139] IL-22 also acts as an inhibitor of cellular differentiation and a protector against cellular damage.[138,140–142] Therefore, the limited IL-22 production in HS may also be related to the destructive nature of the HS inflammation. Finally, IL-22 is a regulator of metabolism.[143]

Among the mediators known to be produced by skin tissue cells, HS lesions show increased expression of IL-36α, IL-36β and IL-36γ, which were mainly localized to keratinocytes.[47,64,144,145] The IL-36 receptor (Figure 4) is expressed by tissue cells including keratinocytes, as well as monocytic immune cells and T cells.[146] IL-36 cytokines are known for their induction of neutrophil-attracting chemokines, specific cytokines and AMPs.[147,148]

Another tissue-cell cytokine highly expressed in HS lesional skin is IL-17C.[149] IL-17C is part of the IL-17 cytokine family.[150] It is induced by proinflammatory cytokines including IL-1β and TNF-α, and to a lower extent by IL-17A, as well as by bacterial components.[151] The IL-17C receptor complex (Figure 4)[151–153] is mainly expressed by epithelial cells including keratinocytes,[151] but is also expressed by Th17 cells.[153] Interestingly, the (autocrine) responses induced by IL-17C in keratinocytes are very similar to those induced by IL-17A/F.[151,154]

Some of the inflammatory cytokines and their target molecules produced in HS lesions are also detectable in the circulation.[47,64,95,97,155–159] They may act systemically and support comorbidities in these patients.[1] Furthermore, they may be useful as indicators of the activation of specific immunological pathways in the skin. They could also enable the identification of patients at risk for specific comorbidities. A range of efforts have been made to identify such biomarkers also beyond cytokines.[52,160,161]