10.5826/dpc.1204a157
Introduction: Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease. Although the pathogenesis remains unclear, at the basis of HS there is an enhancement of the immune and inflammatory response together with a susceptibility to environmental factors. Cytokines dysregulation is crucial in HS severity and progression.
Objectives: the aim of this study was to analyze serum levels of different cytokines focusing on adiponectin concentration and its oligomeric distribution in serum from HS patients compared to both obese and healthy subjects.
Methods: The concentrations of adiponectin and cytokines were measured using ELISA assay; the oligomeric distribution of adiponectin was evaluated through Western Blotting analysis.
Results: Total Adiponectin is statistically higher in HS patients compared to matched controls (28.54 ±4.49μg/mL vs 24.67±3.35 μg/mL, p=0.00). Interestingly, Adiponectin oligomerization state is altered in HS, with an increase of HMW oligomers. Serum levels of PDGF-BB, IL-1b, IL-5, Il-6, IL12, IL13, IL15, IL-17, GMCSF, INFg, VEGF and MCP-1 are statistically higher while IL-1ra and RANTES levels are statistically lower in HS patients compared to healthy controls. Interestingly, adiponectin positively correlates with PDGF-BB, and IL-13.
Conclusions: HS patients have a dysregulated immune homeostasis correlated with altered metabolism. Indeed, our data suggest that Adiponectin and its HMW oligomers are involved in HS representing a potential biomarker of disease. In particular, the specific correlation of adiponectin with PDGF-BB, and IL-13 extends its role in modulation of immune responses suggesting that this adipokine might act regulating the innate immune system rather that the adaptive one.
text/xml
2160-9381
2019
en
Aurora Daniele
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Adiponectin, hidradenitis suppurativa, cytokines, inflammation, immune system.
Adiponectin contributes to the inflammatory milieu in hidradenitis suppurativa
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2021-09-08
2022-10-31
2022-11-29
e2022157
Dermatol Pract Concept
Introduction: Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease. Although the pathogenesis remains unclear, at the basis of HS there is an enhancement of the immune and inflammatory response together with a susceptibility to environmental factors. Cytokines dysregulation is crucial in HS severity and progression.
Objectives: the aim of this study was to analyze serum levels of different cytokines focusing on adiponectin concentration and its oligomeric distribution in serum from HS patients compared to both obese and healthy subjects.
Methods: The concentrations of adiponectin and cytokines were measured using ELISA assay; the oligomeric distribution of adiponectin was evaluated through Western Blotting analysis.
Results: Total Adiponectin is statistically higher in HS patients compared to matched controls (28.54 ±4.49μg/mL vs 24.67±3.35 μg/mL, p=0.00). Interestingly, Adiponectin oligomerization state is altered in HS, with an increase of HMW oligomers. Serum levels of PDGF-BB, IL-1b, IL-5, Il-6, IL12, IL13, IL15, IL-17, GMCSF, INFg, VEGF and MCP-1 are statistically higher while IL-1ra and RANTES levels are statistically lower in HS patients compared to healthy controls. Interestingly, adiponectin positively correlates with PDGF-BB, and IL-13.
Conclusions: HS patients have a dysregulated immune homeostasis correlated with altered metabolism. Indeed, our data suggest that Adiponectin and its HMW oligomers are involved in HS representing a potential biomarker of disease. In particular, the specific correlation of adiponectin with PDGF-BB, and IL-13 extends its role in modulation of immune responses suggesting that this adipokine might act regulating the innate immune system rather that the adaptive one.
Aurora Daniele
2022/10/31
10.5826/dpc.1204a157
e2022157
Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”, Caserta, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli «Federico II», Napoli, Italy
2160-9381
Adiponectin, hidradenitis suppurativa, cytokines, inflammation, immune system.
en
e2022157
Hattori, Y. et al. High molecular weight adiponectin activates AMPK and suppresses cytokine-induced NF-kappaB activation in vascular endothelial cells. (2008) FEBS Lett 582:1719–1724.
Adiponectin contributes to the inflammatory milieu in hidradenitis suppurativa
https://dpcj.org/index.php/dpc/article/download/2019/1824
         Adiponectin Contributes to the Inflammatory
              Milieu in Hidradenitis Suppurativa
        Ersilia Nigro1,2, Rita Polito2, Graziella Babino3, Edi Mattera4, Elisabetta Fulgione3,
        Giovanni Ragozzino4, Vittoria D’Esposito5, Serena Cabaro5, Giuseppe Signoriello6,
                    Pietro Formisano5, Giuseppe Argenziano4, Aurora Daniele2,7


1 Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Università degli Studi della Campania “Luigi Vanvitelli”,
  Caserta, Italy
2 CEINGE-Biotecnologie avanzate, Naples, Italy
3 Dermatology Unit, Università Degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy
4 Department of Internal and Experimental Medicine and Surgery Unit of Internal Medicine, Università degli Studi della Campania
  “Luigi Vanvitelli”, Naples, Italy
5 Department of Translational Medicine, University of Naples Federico II, Naples, Italy
6 Department of Public, Clinical and Preventive Medicine, Medical Statistics Unit, Università degli Studi della Campania “Luigi Vanvitelli”,
  Naples, Italy
7 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli «Federico II», Naples, Italy



Key words: adiponectin, hidradenitis suppurativa, cytokines, inflammation, immune system
Citation: Nigro E, Polito R, Babino G, et al. Adiponectin contributes to the inflammatory milieu in hidradenitis suppurativa. Dermatol
Pract Concept. 2022;12(4):e2022157. DOI: https://doi.org/10.5826/dpc.1204a157
Accepted: March 8, 2022; Published: October 2022
Copyright: ©2022 Nigro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: POR CAMPANIA FESR 2014/2020. project- CUP: B21C17000030007
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Aurora Daniele, PhD, Dipartimento di Medicina Molecolare e Biotecnologie Mediche; Università degli Studi di
Napoli «Federico II»; CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore, 486, 80145 Napoli, Italy. tel.: +39 081 3737856,
fax: +39 081 3737808 E-mail: aurora.daniele@unina.it




  ABSTRACT              Introduction: Hidradenitis suppurativa (HS) is a severe chronic skin disease. Although the patho-
                        genesis remains unclear, at the basis of HS there is an enhancement of the immune and inflammatory
                        response together with a susceptibility to environmental factors. Cytokine dysregulation is crucial in
                        HS severity and progression.
                        Objectives: The aim of this study was to analyze serum levels of different cytokines focusing on adi-
                        ponectin concentration and its oligomers in HS patients compared to both obese and healthy subjects.
                        Methods: The concentrations of adiponectin and cytokines were measured using enzyme-linked
                        immunosorbent assay (ELISA); the oligomeric distribution of adiponectin (low molecular weight
                        (LMW), medium molecular weight (MMW) and high molecular weight (HMW) oligomers)was eval-
                        uated through Western Blotting analysis.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022157                                                                                 1
                      Results: Total adiponectin is statistically higher in HS patients compared to matched controls and
                      obese subjects. Interestingly, Adiponectin oligomerization state is altered in HS, with an increase of
                      HMW oligomers. Serum levels of PDGF-BB, IL-1β, IL-5, Il-6, IL12, IL13, IL15, IL-17, GMCSF, INFγ,
                      VEGF and MCP-1 are statistically higher while IL-1ra and RANTES levels are statistically lower in
                      HS patients compared to healthy controls. Interestingly, adiponectin positively correlates with PDGF-
                      BB, and IL-13.
                      Conclusions: Our data confirmed that the complex network that links metabolism to immune homeo-
                      stasis is dysregulated in HS and that adiponectin and its HMW oligomers are actively involved in this
                      disease. In addition, the correlation between adiponectin and PDGF-BB, and IL-13 extends the role
                      of this adipokine in modulation of the immune response, in particular regulating the innate immune
                      system rather that the adaptive one. Further researches are needed to clarify the complex inflammatory
                      milieu that characterizes HS syndrome.




Introduction                                                        the adiponectin, in patients affected by HS to investigate the
                                                                    potential relationships with metabolic parameters, disease
Hidradenitis suppurativa (HS) is a complex, chronic inflam-         severity and the risk of HS. We examined cytokines, adi-
matory skin disease characterized primarily by a dysregulation      ponectin as potential biomarkers of inflammation in HS.
of the innate immune system and by a chronic inflammation
that is not only restricted to skin but, especially in severe       Objectives
cases, affects different tissues and organs [2,3]. In particular,
the over-activated immune cell infiltration, that is at the basis   To better understand the nature of inflammation in HS and
of HS disease, enhances the inflammatory response through           the potential cross link with adipose tissue (AT), the aim of
the secretion of a considerable quantity of pro-inflammatory        our study was to analyze the expression of different cyto-
(IL-1β, TNFα, IL-17, INF γ) as well as anti-inflammatory cyto-      kines focusing on adiponectin concentrations and its oligo-
kines (IL-10) and chemokines [4-6]. On the other hand, an im-       meric distribution in serum of HS patients respect to both
munological “priming” in HS comes also from environmental           obese and healthy subjects.
factors such as, smoking-related inflammatory mediators and
obesity related pro-inflammatory signals [7]. In particular, in     Methods
obesity, the increased adipose tissue determines a pro-inflam-
matory environment due to the imbalance in production of            Participants
adipokines that contributes to severity and progression of HS       Fifty-three patients (31 females, 22 males), aged 30.0 ± 13.0
disease [8,9]. Recently, it was described a functional interplay    years, were recruited from the Dermatology Unit of the Uni-
among adipose tissue and other organs and tissues whom              versità degli Studi della Campania “Luigi Vanvitelli”. Sub-
dysregulation has a key role in inflammation. Indeed, adipose       jects were excluded from our study if they met any of the
tissue is an endocrine organ that produces several adipocyto-       following criteria: age < 18 years, body mass index (BMI)
kines among which adiponectin exerts multivalent beneficial         < 17 or > 35, major metabolic disorders (type 2 diabetes,
functions; it is abundantly secreted in serum where it circu-       cardiovascular disorders, metabolic syndrome), the presence
lates as oligomers of different molecular weight: low molec-        of concomitant inflammatory cutaneous or systemic disor-
ular weight (LMW), medium molecular weight (MMW) and                ders and the presence of cancer; were excluded also the pa-
high molecular weight (HMW) [10]. The HMW are the most              tients receiving any systemic treatment which could interfere
biologically active oligomers [11]. Adiponectin is involved in      with the studied parameters. Disease staging was based on
the regulation of energy homeostasis, insulin sensitivity and       the three-degree scale proposed by Hurley. The mean BMI
inflammation [12]; interestingly, adiponectin expression is         of 29.67 ± 6.1 kg/m2 qualified our patients as overweight.
up-regulated in different inflammatory diseases and in some         The smoker rate amounted to 62.3%. Forty-two healthy
auto-immune diseases, while is down-regulated in metabolic          volunteers were recruited from the CEINGE staff, they aged
diseases [13]. Regarding hidradenitis, serum adiponectin con-       33 ± 12.0 years old and constituted the control group
centrations were found to be significantly lower, while the lev-    (BMI = 23.3 ± 3.0); 53 obese subjects, aged 33±12 years
els of the other adipocytokines have been found significantly       old (BMI = 48.4 ± 9.4), were recruited from the Founda-
higher than in controls [14,23].                                    tion “Salvatore Maugeri” Telese, Italy [15]. All HS patients
    The aim of this study was to analyze the serum concentra-       fulfilled the established HS diagnostic criteria. All subjects
tions of 27 cytokines and the most abundant adipocytokine,          signed an informed consent form. The study was approved



2                                                                       Original Article | Dermatol Pract Concept. 2022;12(4):e2022157
by the Ethic Committee of the Università degli Studi della              Statistical Analysis
Campania “Luigi Vanvitelli” (Prot. 12478/20).                           Data is expressed as average ± standard deviation (SD) and
                                                                        median. The meanings of the differences in biochemical
Anthropometric and Biochemical Measurements                             parameters between the groups were determined using the
Blood samples from 53 HS patients, 42 healthy subjects and              Mann-Whitney test and the Chi-square test. To evaluate the
53 obese subjects were collected after a 12-hours overnight             relationship with median adiponectin levels, multiple logistic
fasting period and centrifuged to collect serum. Serum ali-             regression was performed. A P value <0.05 was considered
quots were immediately frozen in liquid nitrogen and stored             to indicate statistically significant results.
at -80°C. For all participants total cholesterol, triglycerides,
glycemia, C-Reactive Protein were measured (Table 1). The
                                                                        Results
concentration of total adiponectin was measured in triplicate
by an enzyme-linked immunosorbent assay (ELISA) as previ-               Baseline Features and Serum Levels of Adiponectin
ously described [16].                                                   in HS Patients
    The levels of 27 cytokine species (PDGF-BB, IL1β,                   The anthropometric and biochemical characteristics of HS
IL1ra, IL2, IL4, IL5, IL6, IL7, IL8, IL9, IL10, IL12, IL13,             patients, sex and age-matched obese and healthy subjects are
IL15, IL17, Eotaxin, FGF, GCSF, GMCSF, INFγ, IP10,                      shown in Table 1. We found statistically significant differ-
MCP-1, IP1α IP1β, RANTES, TNFa , VEGF) were mea-                        ence in BMI between HS patients and controls (29.67 ± 6.12
sured in 30 HS patients and in 39 healthy controls using a              versus 23.3 ± 3.04, P < 0.00) as well as for total adiponectin
commercially available kit (Bio-Plex Pro™ Human Cyto-                   serum levels (28.25 μg/ml ± 4.49 versus 24.67 μg/ml ± 3.35,
kine 8-plex Assay). The assay was performed according to                P < 0.01); both parameters result significantly higher in HS
the manufacturer’s instructions and the concentrations of               patients compared to controls. The statistical analysis indi-
cytokines were calculated by comparing reads with a 5-pa-               cated that the increase of adiponectin levels in HS is inde-
rameter logistic standard curve using a Bioplex-200 instru-             pendent from BMI and sex, 2 potential confounding factors.
ment (Bio-Rad).                                                         Statistical analysis did not reveal significant difference in ad-
                                                                        iponectin concentrations among the HS groups based on the
Western Blotting Analysis of Serum Adiponectin                          three Hurley degrees of disease severity. HS Hurley degree of
Five micrograms of total serum proteins were treated and                HS patients are reported in Table 1: 30.2% of the patients
subjects to electrophoresis as previously described [17]. The           have a Hurley I, 52.8% Hurley II and 17.0% Hurley III de-
blots were developed by ECL (Amersham Biosciences) with                 gree of disease severity.
the use of Kodak BioMax Light film and digitalized with a                     As in literature was reported an opposite trend and to
scanner (1.200 dpi) and analyzed by densitometry with the               further validate the findings on concentration of ­adiponectin,
ImageJ software. Each serum sample was tested 2 times in                we measured the levels of this adipokine in a cohort of 53
duplicate.                                                              obese patients; as shown in Table 1, the comparison of


        Table 1. Clinical, biochemical and anthropometrical characteristics of HS, obese patients
                                          and healthy subjects.
                                                             HS patients             Obese subjects              Controls
                                                               (N 53)                   (N. 53)                   (N 42)           P
 Sex (F), N (%)                                                   31 (53.8)             33 (62.3)                20 (47.6)        0.38
 Age mean (±SD), years                                             30±13                  33±12                   33±12           0.37
 BMI mean (±SD)                                              29.67 ± 6.12               48.4 ± 9.4             23.3 ± 3.04        0.00
 Cholesterol mean (±SD) (mg/dL)                             203.54 ± 44.16           169.94 ± 37.21          191.48 ± 35.22       0.00
 Triglycerides mean (±SD) (mg/dL)                           103.62 ± 36.97           146.81 ± 102.54          82.86 ± 50.31       0.00
 Glycemia mean (±SD) (mg/dL)                                      94 ± 19                87 ± 28                 86 ± 17          0.17
 C-Reactive Protein mean (±SD) (mg/L)                            6.87 ± 8.36           8.23 ± 8.48                   -            0.41
 Hurley IN (%)                                                    16 (30.2)                  -                       -              -
 Hurley II N (%)                                                  28 (52.8)                  -                       -              -
 Hurley III N (%)                                                 9 (17.0)                   -                       -              -
 Adiponectin mean (±SD) (γg/mL)                              28.54 ± 4.49              20.06 ± 4.71            24.67 ± 3.35       0.00

BMI = body mass index; HS = hidradenitis suppurativa; SD = standard deviation.



Original Article | Dermatol Pract Concept. 2022;12(4):e2022157                                                                           3
                      A                         HS patients         Obeses                       Controls




                      B                                                               HS    Obeses       Controls
                                                4
                                                      a
                                               3,5
                                                                c
                                                3
                             Optical density




                                               2,5
                                                                     a
                                                2
                                                                                  c
                                               1,5         b

                                                1                          b                 a              a

                                               0,5                                                   b

                                                0
                                                          HMW            MMW                       LMW

                     Figure 1. Western blotting analysis shows that adiponectin HMW and MMW oligomers
                     are statistically higher in serum from HS patients compared to obese and healthy subjects.
                     (A) Representative WB image of adiponectin different oligomers (HMW, MMW, LMW) from
                     four HS patients, four obese subjects and four controls. (B) Graphical representation of pixel
                     quantization of adiponectin oligomers analysed in 53 HS patients, 53 obese subjects and
                     42 controls. For other details see materials and methods. P < 0.05.



biochemical parameters between HS patients and obese sub-             IL12, IL13, IL15, IL-17, GMCSF, INFγ, VEGF and MCP-1
jects showed a statistically differences in BMI (29.67 ± 6.12         levels were statistically higher while IL-1ra and RANTES
versus 48.4 ± 9.4, P < 0.00) as well as in adiponectin levels;        levels were statistically lower in the serum of HS patients
these latter are higher in HS than in obese patients (28.25 μg/       compared to healthy controls (Table 2).
ml ± 4.49 versus 20.06 μg/ml ± 4.71, P < 0.00).                           Next, to investigate whether adiponectin is functionally
                                                                      related with any tested cytokines, we divided the HS patients
Oligomeric Distribution of Adiponectin                                in two subgroups using the median value of adiponectin con-
in HS Patients                                                        centration (27.8 μg/mL) as an arbitrary cut-off. According to
To better investigate the involvement of adiponectin in HS            adiponectin concentrations, patients with higher adiponectin
patients, we examined the oligomeric profile of this adipo-           concentrations (ie with values above the median) represented
kine through the visualization of HMW; MMW and LMW                    subgroup 1 and patients with lower adiponectin concentra-
oligomers. Western blot evidenced that the HMW and                    tions (ie with values under the median) represented subgroup
MMW adiponectin oligomers are increased in serum of HS                2. Statistical analysis performed using the univariate model
patients if compared to obese and healthy subjects (Figure 1,         showed that the patients with higher levels of adiponectin
P < 0.05).                                                            (subgroup 1) have also significantly higher PDGF-BB and a
                                                                      similar trend versus IL-13 (Table 3).
Cytokine Concentration in HS Patients
and Healthy Controls
                                                                      Conclusions
To better explore the inflammatory milieu in serum from
HS patients, we analyzed a panel of 27 different cytokines            Hidradenitis (HS) is a severe chronic inflammatory skin
(PDGF-BB, IL1β, IL1ra, IL2, IL4, IL5, IL6, IL7, IL8, IL9,             disease primarily due to the alteration of immunity and to
IL10, IL12, IL13, IL15, IL17, Eotaxin, FGF, GCSF, GMCSF,              chronic inflammation [2,18]. A functional interconnection
INFγ, IP10, MCP-1, IP1α, IP1β, RANTES, TNFα, VEGF). We                between immune system and adipose tissue, link observed in
tested 30 HS patients and 39 controls. The results demon-             patients affected by metabolic disorders in which the dysreg-
strated that, among the others, PDGF-BB, IL-1β, IL-5, Il-6,           ulation of energy metabolism negatively affects the immune



4                                                                          Original Article | Dermatol Pract Concept. 2022;12(4):e2022157
                      Table 2. Cytokine levels (pg/ml) in HS patients and healthy subjects.
                Parameters                                  Controls (N 39)                       HS patients (N 30)                P
 Sex N (%)                                         F              17 (44%)                             19 (63%)                   0.10
                                                  M               22 (56%)                             11 (37%)
 Age, mean (±SD)                                                  33.8 (6.8)                          29.6 (13.5)                 0.096
 BMI, mean (±SD)                                                  25.5 (3.7)                           26.6 (3.8)                 0.23
 IL-1β, mean (±SD)                                                 2.0 (0.5)                            2.3 (0.5)                 0.014
 IL-12, mean (±SD)                                                11.3 (1.3)                           13.5 (3.9)                 0.002
 IL-13, mean (±SD)                                                 5.5 (1.1)                            8.4 (4.1)               <0.001
 IL-15, mean (±SD)                                               347.2 (25.0)                        390.3 (38.4)               <0.001
 IL-17, mean (±SD)                                                25.0 (3.9)                           27.2 (5.2)                 0.048
 GM-CSF, mean (±SD))                                              12.8 (0.7)                           14.5 (1.5)               <0.001
 IFNγ, mean (±SD)                                                 13.3 (3.1)                           18.6 (4.7)               <0.001
 MCP-1 (MCAF), mean (±SD)                                        36.9 (15.0)                          56.1 (31.7)                 0.001
 RANTES, median (IQR)                                  6833.4 (5469.2, 8214.1)               45145.1 (20829.6, 93670.0)         <0.001
 PDGF-BB, median (IQR)                                 1638.5 (1180.5, 1991.2)                 2306.6 (1701.6, 3208.0)          <0.001
 IL-1ra, median (IQR)                                    371.5 (333.0, 446.4)                    333.0 (257.0, 400.0)             0.036
 IL-5, median (IQR)                                         52.3 (49.0, 55.5)                      58.5 (52.3, 67.1)              0.002
 IL-6, median (IQR)                                              7.6 (7.0, 8.1)                     9.0 (7.8, 10.2)             <0.001
 VEGF, mean (SD)                                                 417.6 (40.2)                        452.3 (52.7)                 0.003

BMI = body mass index; HS = hidradenitis suppurativa; SD = standard deviation. Acronym list: IL (interleukin); Granulocyte-­Macrophage
Colony-Stimulating (GM-CSF); Interferon (INF); Monocytes Chemoattractant Protein(MCP); Platelet-Derived Growth Factor-BB
­
(PDGF-BB); Vascular Endothelial Growth Factor (VEGF).



    Table 3. Univariate analysis of anthropometric, clinical parameters and cytokines levels (pg/ml)
      on the basis of adiponectin levels: median value of adiponectin (27.8 μg/ml) was used as an
                                            arbitrary cut-off.
                                                             Adiponectin ≤ 27.8                     Adiponectin > 27.8              P
            Parameters                                                 N = 14                              N = 16
 Sex                                     M, N (%)                     7 (50%)                             4 (25%)                  0.16
                                         F, N (%)                     7 (50%)                             12 (75%)
 Age, mean (±SD)                                                     30.1 (12.1)                         29.3 (15.1)               0.87
 BMI, mean (±SD)                                                      27.3 (3.7)                         26.0 (4.0)                0.36
 PDGF-BB, (median) (IQR)                                   2984.9 (2226.8, 3463.2)                1823.9 (1306.3, 2507.5)          0.020
 IL-5, median (IQR)                                               61.5 (55.5, 65.7)                   55.5 (48.1, 68.1)            0.18
 IL-13, median (IQR)                                                8.8 (7.3, 9.7)                      5.8 (4.9, 9.6)             0.05
 GM-CSF, median (IQR)                                             14.7 (13.9, 15.5)                   13.5 (12.7, 15.8)            0.15
 Hurley                                       I                       5 (36%)                             6 (38%)                  0.98
                                             II                       5 (36%)                             6 (38%)
                                             III                      4 (29%)                             4 (25%)



system and viceversa. Indeed, in obese or overweight people              component of the body protective systemic response to the
there is a greater frequency of autoimmune diseases such as              chronic inflammatory processes and immune system alter-
rheumatoid arthritis, type I diabetes and HS [24]. This func-            ations [17,18,21].
tional interconnection is guaranteed by the hormonal activ-                    In this study, to investigate the nature of the inflammatory
ity of the adipose tissue through the secretion of adipokines            milieu in HS and the potential contribute of adipose tissue, we
such as adiponectin. In literature, numerous studies support             analyzed several cytokines focusing on the most abundant ad-
the hypothesis that high levels of adiponectin represent a key           ipokine, ie adiponectin and its oligomeric profile. Interestingly,



Original Article | Dermatol Pract Concept. 2022;12(4):e2022157                                                                             5
we found increased levels of adiponectin and HMW oligo-            reported in one study [30]; in two other studies no statistical
mers in HS patients compared to both healthy and obese             difference was found [31,32].
subjects independently from BMI. To our knowledge, there              Finally, for the first time, we correlated cytokines expres-
are two studies describing adiponectin concentration in HS         sion level to adiponectin concentration. We found that adi-
that found decreased serum level of adiponectin in the pa-         ponectin correlates with PDGF-BB, and IL-13 but not with
tients [22,23]. The discrepancy with our results may be traced     IL-17, IL-1β, and INFγ suggesting that adiponectin function
back to clinical and biochemical differences of the considered     might be related to the innate immune system activation
patients: the study by Malara et al. analyzed patients with a      rather that the adaptive one, exerting anti-inflammatory ac-
very high BMI (33 versus 29.6 of our cohort), while Gonza-         tions. Previously, adiponectin has been demonstrated to di-
lez-Lopez considered a cohort of patients with a more severe       rectly and specifically bind PDGF-BB in smooth muscle cells
clinical phenotype of HS [22,23]. It is to notice, however, that   suppressing their proliferation and migration [33] suppress-
we excluded that BMI might represent a confounding factor          ing the development of atherosclerosis, promoting inflam-
for adiponectin expression in HS patients; indeed, HS patients     mation. Arita et al. demonstrated that the inhibitory effects
are more likely to have obesity and metabolic syndrome and         of adiponectin towards PDGF-BB result in suppression of
overweight people have a greater incidence of HS [24].             vasculogenesis and inflammation [33]. The association be-
    In addition, although the significance of the molecular        tween adiponectin and PDGF-BB in HS patients suggests
distribution of adiponectin is still largely unknown, it has       that the adipokine probably counteracts the inflammatory
been shown that the HMW oligomers have a stronger bi-              process triggered by the disease.
ological meaning and is the most important contributor to             As IL-13 has been described as anti-inflammatory fac-
adiponectin functions [10]. Our findings that HS is associ-        tor in the adipose tissue, the direct correlation with ad-
ated with high circulating adiponectin levels, combined with       iponectin further confirms that adiponectin is acting as
a shift towards the HMW forms reinforce the hypothesis that        anti-inflammatory molecule [34]. In addition, IL-13 has been
adiponectin has a strong functional role in regulating inflam-     involved in the maintenance of macrophages in an anti-in-
mation in HS. The specificity of adiponectin role in HS is con-    flammatory state as M2 phenotype supporting the hypothe-
firmed also by the significant difference of its concentrations    sis that adiponectin might participate in the regulation of the
that we found in the two populations, HS and obese subjects.       innate immune response [35].
    Next, in this study, we analyzed different cytokine expres-       There are two main limitations in the present study, one
sion previously reported to spill-over from the skin lesions       is the relatively small number of patients and the other is the
into the systemic circulation resulting in heightening risk for    absence of a large cohort of severe patients. In addition, the
systemic inflammation in HS patients [1]. Among the others,        great heterogeneity in age, gender, environmental factors and
we found that PDGF-BB, IL-1β, IL-5, Il-6, IL12, IL13, IL15,        potential comorbidities among the HS analyzed patients in
IL-17, GMCSF, INFγ, VEGF and MCP-1 levels are statisti-            different studies may be at the basis of the variability found
cally higher in HS patients while IL-1ra and RANTES levels         in the expression of cytokines.
are statistically lower in the serum of HS patients compared          In conclusion, our data confirmed that the complex net-
to healthy controls. Serum cytokine levels are very often al-      work that links together metabolism to immune homeostasis
tered in HS patients [25,23]. In accordance with our data,         is dysregulated in HS and that adiponectin and its HMW
the levels of the pro-inflammatory IL-17 cytokine, whose pro-      oligomers are not only actively involved in the HS but that
duction is made by neutrophils and Th17 cells, is increased        interacts with the complex inflammatory systemic milieu
in HS patients [26,27]. IL-17 is crucial in determining the in-    made by pro-inflammatory cytokines. In addition, the cor-
flammatory process of HS, inducing the expression of other         relation between adiponectin and PDGF-BB, and IL-13 ex-
pro-inflammatory cytokines, such as IL1β and TNFα and              tends the role of this adipokine in modulation of the immune
stimulating the activation of adaptive immune cells [1,28]. On     response suggesting that adiponectin might act regulating the
the other hand, one study found no differences in IL-17 lev-       innate immune system rather that the adaptive one. Further
els between patients and controls [29]. Regarding IFN-γ, no        researches are needed to clarify the complex inflammatory
statistically decrease was found in the serum of HS patients       milieu that characterizes HS syndrome.
while a significant difference was found in another study [7].
    Although not significant, our data also evidenced that         References
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