The modulation of the NF-κB pathways has frequently been described as “pro-inflammatory”, largely due to the key role of NF-κB in the pro-inflammatory genes expression including cytokines, chemokines, and adhesion molecules [
42,
43]. Many findings demonstrated that epithelial cells in the glandular sites of patients affected by pSS are able to release factors that address the chemoattraction of lymphocytes and promote chronic inflammatory responses [
12,
15,
16,
24,
25,
26]. NF-κB pathway modulation was therefore investigated in pSS, highlighting a role in regulating the production of pro-inflammatory cytokines, leukocyte enrolment, or cell survival [
17,
18,
25,
26,
44]. In pSS, the NF-κB activation cascade can be modulated at different levels [
30]. Considering the correlation with the biopsy focus score, grade of infiltration and evaluated disease activity, phosphorylated IKKε, responsible for the degradation of IkB proteins, were significantly and positively correlated with NF-κB levels in pSS [
4]. The levels of B-Cell Activating Factor (BAFF) and those of numerous pro-inflammatory cytokines, all regulated by NF-κB signalling, are augmented in pSS [
45]. Nucleotide polymorphisms in NF-κB pathway genes have been linked with pSS [
46], and a specific mutation in the Ikα-826T, one of the promoters of a member of the inhibitory IkB complex, was associated with susceptibility of pSS [
47,
48]. Numerous small molecule inhibitors of the NF-κB signalling pathways are currently commercially available for use, and NF-κB modulators are under study in clinical trials for pSS treatment [
19,
25,
30,
49,
50,
51,
52,
53,
54]. Many preclinical studies have already analysed the role of NF-κB signalling in the glandular tissue in pSS. The pSS SGECs have been recognized to have an active NF-κB pathway. The phosphorylated forms of IKKε, IκBα, and NF-κB were expressed in the ductal cells in minor SGs derived from pSS patients [
19]. By stimulating the Toll-Like Receptor 2 (TLR2) in SGECs, IL-2 production was induced through the NF-κB cascade in pSS SGECs [
49,
50,
51]. SGECs treated with the anti-Ro/SSA autoantibodies isolated from pSS patients showed a progressive increase in constitutive NF-κB activation, and transfection of SGECs with IκBα in SGECs treated with anti-Ro/SSA led to a remarkable production of pro-inflammatory cytokines and an enhanced apoptosis [
25]. Furthermore, recent findings showed that gene silencing of the natural NF-κB inhibitor TNF Alpha Induced Protein 3 (TNFAIP3) in keratin-14-positive epithelial cells, promoting the activation of the constitutive NF-κB cascade, induces the initial phases of pSS, leading to a reduced production of saliva and lymphocyte invasion in the SGs [
52]. This effect is likely related to the calcium pathway in the acinar cells, since calcium signalling has an important role in NF-κB pathway activity [
53,
54]. A list of NF-κB small molecule inhibitors tested in pSS is reported in
Table 1.
The Key Role of IκBα in NF-κB Modulation in pSS
Among the well-characterized regulators of NF-κB activation in SGEC, IκBα is particularly important for the pathogenesis of pSS. The concept that IκBα expression negatively regulates NF-κB DNA binding activity was demonstrated by the fact that reduced IκBα overlaps with nuclear translocation of the NF-κB and the appearance of NF-κB activity [
55]. For SGs, adenoid cystic carcinoma of human SGs cell lines, stably transfected with the mutant IκBα expression vector (IκBαM) share an effectively cancelled constitutive and liposaccharide-induced NF-κB activity, concomitantly with a significantly diminished VEGF gene and protein expression. This effect leads to a lower endothelial cell mobility and, thus, might represent a promising anti-angiogenesis strategy in adenoid cystic carcinoma (ACC) therapy [
56]. In pSS SGEC, abnormal levels of IκBα were detected in comparison with those in healthy subjects, showing a clear reduction of IκBα in salivary tissues from active pSS patients [
19]. This was confirmed in biopsy specimens, where a moderate IκBα positive staining located in the cytoplasm of acini and ductal cells was revealed in healthy controls, whereas in pSS salivary gland biopsies the cytoplasmic positivity for IκBα was very weak [
19]. All of this suggests that the production of proinflammatory cytokines occurs through the persistent activation of NF-κB signalling [
17,
18,
25,
26]. In addition, a reduced gene and protein expression of IκBα was demonstrated in monocytes from pSS patients in comparison with healthy subjects, suggesting that the reduced expression of this NF-κB inhibitor may reflect an increased inflammatory response [
26]. Specifically, published data show that mutations in IκBα are linked to inflammatory autoimmune disorders. An 8-bp insertion in the promoter region of IκBα represents a protective factor against the development of primary progressive multiple sclerosis [
57]. Klein et al. showed that IκBα polymorphisms might also be associated with Crohn’s disease [
58], SLE [
59] and pSS [
47,
48]. In particular, mutant mice, that have defective IκBα expression, showed a shorter lifetime, hypersensitivity to septic shock and altered T cell development, all features of pSS [
47,
48]. Furthermore, overexpression of the NF-κB repressor, IκBα, determines an inhibitory effect on the production of STAT-4 protein, a transcription factor activated by interleukin 12 whose gene polymorphism was recently linked to pSS [
60,
61].
NF-κB signalling activation and termination is secured by various regulatory processes. In view of the well-characterized links between NF-κB and pSS disease, disentangling the complexity of NF-κB modulation is an essential goal in order to find effective, more specific therapeutic agents for the treatment of pSS.