TLR4 and systemic sclerosis: In fact, the link between monocytes, TLR4 activation and the downstream IFN response with SSc pathogenesis is supported by several observations: (i) circulating monocytes have been indicated as one prominent leukocyte subset playing a role in the pathogenesis of SSc (52–55); (ii) circulating SSc monocytes are characterized by an increased type I IFN signature (11, 12, 16) (iii) TLR activation may represent the connection between immune activation in SSc and tissue fibrosis (7, 10, 52, 56).