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.