5. SAT in inflammatory skin diseases
Inflammatory processes within the
SAT of the skin differ from those in the epidermis and dermis. There is
limited research on this subject and most evidence comes from studies on
psoriasis (123). Psoriasis is associated with an increased risk of
cardiovascular and immunometabolic disorders, notably obesity (124,
125). The increased production of pro-inflammatory adipokines and
decreased production of anti-inflammatory adiponectin in obesity may
predispose individuals to develop psoriasis (126, 127). Animal models
also indicate that diets high in saturated fatty acids can promote
IL-17-mediated immune responses, leading to increased susceptibility to
psoriasis (128, 129).
Dermal sclerosis is another pathogenic process that might be aided by
aberrant responses in AT. Recent studies suggest the involvement of ECM
produced by WAT-derived myofibroblasts in scleroderma pathogenesis (130,
131). As of yet, other neutrophilic and fibrotic diseases such as
hidradenitis suppurativa (HS) have not yet been linked to AT; clinical
evidence, namely the high incidence of obesity in HS patients and the
distribution of inflammatory infiltrates in the follicular epithelium,
strongly suggest a role of SAT (132, 133).
Inflammatory conditions primarily
originating and taking place in SAT are grouped under the term
“panniculitis”. Panniculitides encompass a range of heterogeneous
etiologies, including infection, trauma, connective tissue diseases,
vasculitis, and certain types of cancer (Table 2). Their classification
considers location, lesion etiology, and histopathology. The latter
takes into account whether SAT infiltration is septal or lobular and
whether it is accompanied by vasculitis (134-136).
Despite diverse etiologies, the cellular and molecular pathomechanisms
underlying panniculitis remain poorly characterized. Therapeutic
approaches remain widely nonspecific, including non-steroidal
anti-inflammatory drugs, oral potassium iodide, dapsone, and
hydroxychloroquine (137-141).
Panniculitides can originate either as primary pathologies within AT or
as secondary manifestations of systemic diseases. For instance, erythema
nodosum (EN), the most common type of panniculitis, may be idiopathic or
triggered by infections, sarcoidosis, Crohn’s disease, or other
conditions (142). In rare cases, neutrophilic dermatoses or pregnancy
can induce an EN eruption (143). The pathogenesis of EN is postulated to
involve type III or IV hypersensitivity reactions. There is evidence
suggesting a pathogenic role of neutrophils via their production of
reactive oxygen intermediates, which induce tissue damage. (144-147).
This process ultimately results in increased expression of adhesion
molecules, VEGF, and cytokines (i.e., TNF-α, IL-6, and IL-8) both
locally and systemically, facilitating immune cell migration to the SAT
septae (148) (Fig 6A).
Erythema Induratum of Bazin (EIB) is a lobular panniculitis with
lymphocytic vasculitis (149). It is recognized as a multifactorial
disease associated with several triggers, including infection with
tuberculosis (150). Similar to EN, type III and IV hypersensitivity
reactions are hypothesized to play a role in EIB (149) (Fig 6B).
Lupus panniculitis is also a predominantly lobular process with
lymphocytic vasculitis and mucin or calcium deposition. The infiltrating
cells consist mainly of T-cells, B-cells, and macrophages (151). Partial
deficiency in C4, which causes defective opsonization of immune
complexes and disease pathogenesis has been linked to some cases of
early-onset lupus (152).
6. Neoplastic
processes in SAT
Beyond inflammatory processes, SAT can also harbor neoplasms,
originating either from SAT-resident cells or secondary
infiltration/metastasis. The most common primary SAT neoplasms are
benign lipoma (153), while malignant liposarcoma is quite rare (154,
155).
Most primary cutaneous lymphomas, whether of the T cell- (CTCL) or
B-cell-lineage (CBCL) (156-158), typically develop in the dermis and may
subsequently extend to the SAT. In contrast, certain lymphomas, such as
intravascular B-cell lymphoma, can have their primary origin in
different target organs, including SAT (159). However, only a few
lymphomas have their primary origin in SAT. Subcutaneous
panniculitis-like T-cell lymphoma (SPTCL) specifically involves the
subcutis, characterized by neoplastic T-cells rimming fat cells (157,
160). Two distinct types of SPTCL have been identified: (i) SPTCL with
an α/β T-cell receptor (SPTCL-AB), which is characterized by a
CD4−CD8+CD56− phenotype, and (ii) the highly aggressive SPTCL with a γδ
T-cell phenotype (SPTCL-GD), characterized by a CD4−CD8− phenotype with
variable CD56 expression (160). An investigation of SPTCL skin samples
showed significantly increased expression of the tolerogenic enzyme
indoleamine 2,3-dioxygenase (IDO-1) and Th1-specific cytokine, INFγ
(146). It is suggested that IDO-1 overexpression creates an
immunosuppressive environment conductive to SPTLC development (146).
However, the clonal specificity and underlying mechanisms of SPTCL
development remain largely unknown.