*Role of TLRs in the NF-*κ*B-Mediated Inflammatory State in pSS*

Several authors now agree that TLRs trigger an intracellular cascade of molecular events, which has, as its final step, NF-κB activation. Active NF-κB determines the transcription of inflammatory cytokine genes responsible for the exacerbation of inflammation [73]. Studies conducted on experimental animal models confirm that an intensely inflammatory microenvironment could be the basis of autoimmune diseases [88]. This scenario seems to be plausible also for pSS. A recent study reported that TLR-7 and its downstream signalling factors are strongly expressed in labial SG of pSS patients. The authors observed that TLR-7 downstream molecules are expressed in pSS SGEC after TLR-7 ligand stimulation in vitro, inducing the activation of the NF-κB pathway, which elicits the release of inflammatory factors such as IFN-α and IFN-γ [89]. Furthermore, Kwok et al. demonstrated an increased expression of TLR2, TLR4, and TLR6 in pSS SGs, in association with IL-17, IL-6, and IL-23 over-expression, factors that promote T helper17 (Th17) differentiation and amplification. The signalling pathway starts with TLR2 stimulation, which induces a cascade that involves the activation of TLR4 and TLR6. This determines the production of IL-17 and IL-23, which, as demonstrated by the authors, occurs through IκBα phosphorylation, the IL-6, signal transducer and activator of transcription 3 (STAT3), and NF-κB pathways [90]. However, the ligands that eventually activate TLR2 in the context of pSS are still doubtful and little known. Using peptidoglycan (PNG) as stimulus for TLR2 activation, an increased expression of immune mediators (ICAM-1, CD40, and MHC-1) was observed in SGECs derived from pSS patients and controls [82]. In a corroborative study using SGEC from pSS patients, TLR2 drove the NF-κB-dependent secretion of IL-15 [50,51] as confirmed using antibodies anti-TLR2 to block IL-15 secretion [50,51]. Furthermore, by using the dominant-negative inhibitory IκBα vector to inhibit NF-κB activation, TLR2-dependent IL-15 production was reduced, suggesting a transcriptional level control [50,51]. Therefore, this study underlines the importance of the TLR2/IL-15/ NF-κB pathway as a strong potential candidate for the therapeutic modulation of pSS, ameliorating both local and systemic pSS disease manifestations [50,51] A schematic representation of the TLR2 molecular pathway activation in pSS is reported in Figure 4.

**Figure 4.** Schematic representation of the Toll-Like Receptor 2 (TLR2)/IL-15/NF-κB pathway in pSS SGEC. TLR2, in response to pro-inflammatory stimuli, activate the NF-κB pathway; in the nucleus, the active NF-κB promote IL-15 gene transcription; thus, incrementing inflammatory disorders in SGs of pSS patients.
