Table 1.

Alarmins involved in SSc pathogenesis.

Alarmins	Biological Activities (Target Cells)	Serum Levels in SSc	SSc Pathogenesis and References
HMGB-1 (nuclear)	Nuclear/transcriptional regulator Increased expression of genes for proinflammatory factors (neutrophils) Induction of cytokine and chemokine (monocytes, DCs, macrophages, and endothelial cells). Transendothelial migration (monocytes). Proangiogenic; upregulation of adhesion molecules (endothelial cells). Proliferation of naive T lymphocytes; Th1 polarization (T lymphocytes). Procoagulant activity (platelets).	Increased	Promotes pulmonary, renal, and myocardial fibrosis; endothelial damage; coordinate micro thrombosis [57,71,73].
IL-33 (nuclear)	Intranuclear gene regulator Initiation of innate and adaptive type 2 immune responses with the production of IL-4, IL-5, and IL-13. Polarization of M2 macrophages, proliferation of eosinophils, production of IgE, proliferation, and activation of T helper 2 and group 2 innate lymphoid cell (ILC2) (macrophages, ILC2s, mast cells, Th2 cells, eosinophils, basophils, and dendritic cells). Activation and migration of neutrophils to sites of infection (neutrophils).	Increased	Stimulates fibroblast activation; Induces tissue fibrosis (lung, skin); altered microcirculation; immune abnormalities (Tregs transdifferentiation) [108,109,110,111,112,113,118].
IL-1α (nuclear)	IL-1α binds to chromatin and controls homeostatic functions of the cell, like transcription, proliferation, differentiation, or cell death. Physiological manifestations of IL-1 signaling include fever, hypotension, vasodilation, and increased sensitivity to pain. Apical driver of cutaneous inflammation, colon inflammation and cancer, cardiovascular disease, and neural inflammation.	NA	Stimulates production of pro-collagen; regulates fibroblast–myofibroblast differentiation; stimulate the production of IL-6 (profibrotic) and PDGF (chemotactic for inflammatory cells); promotes the viability of fibroblasts [130,131,132,133,134,135,136,137,138].
α- and β- defensins (granule-derived)	Antimicrobial activity. Altered levels of defensins are observed in response to infection, inflammation, angiogenesis or tissue damage. HBDs are chemoattractants for numerous cell types, increase cell proliferation and accelerate angiogenesis and wound healing.	Reduced levels in comparison to healthy controls, but increasing levels from early to late-stage SSc	Possible involvement in vasculopathy [144,145,146,147,148].
LL-37 (granule derived)	Antimicrobial activities against bacteria, viruses, fungi, and parasites; chemotactic; pro- and anti-inflammatory activities and	Increased	Increased in SSc fibroblasts; Inhibits apoptosis of dermal fibroblasts in SSc [150,151,152].
HSP-70 (cytoplasmic)	Stimulates both the innate and adaptive immune systems. The recognition of Hsp70 by immune cells causes initiation of signal transduction which results in the subsequent release of cytokines, including IL-1β, IL-6, IL-12 (macrophages), IFN-γ (T cells), IL-10 (monocytes), and TNF-α (DCs).	Increased	Marker of oxidative stress and disease severity in SSc [153,154,155].
S100 (cytoplasmic)	S100A7 chemotactic inflammatory protein (neutrophils, CD4 T lymphocytes); antibacterial activity in wounds. Dual impact of S100A8/A9 (calgranulin A and B, respectively) on the outcome of inflammatory responses. The secondary release after a preceding stimulus has amplifying effects. Under sterile stress conditions hyporesponsiveness to subsequent inflammatory stimuli.	Increased	Salivary marker in SSc patients with pulmonary involvement [157]. Pro-inflammatory activity on keratinocytes leading to alveolitis, telangiectasia and pitting scars in SSc [158]. Possible biomarker for ILD [162]. S100A9 could contribute to the development of tissue fibrosis in SSc trough fibroblast proliferation and production of connective tissue growth factor [164].