S100A8 is expressed in high amounts in neutrophils and in activated macrophages. Although reported as a proinflammatory protein that activates cytokine production via TLR-4 and/or RAGE ligation, our recent studies challenge this concept. We found that S100A8 efficiently scavenges oxidants generated by activated leukocytes (peroxide, nitric oxide, hypohalous acids) and is likely protective in human asthma. Asthmatic sputum contains novel S100A8 oxidation products that confirm its scavenging capacity in vivo. Moreover, S100A8 suppressed induction of acute murine asthma, partially by inhibiting mast cell activation by scavenging reactive oxygen species (ROS) critical for activation. Importantly, induction of S100A8 is IL-10-dependent and expression in macrophages enhanced by corticosteroids, characteristics of anti-inflammatory responses.

Inhalation of S100A8 alone did not promote inflammation, but this potently suppressed acute lung injury (ALI) in mice provoked by LPS inhalation. Neutrophil influx and mast cell activation were inhibited, concomitant with suppression of cytokines, chemokines and the acute phase reactant SAA3. S100A8 reduced NF-kB mRNA levels increased by LPS, and elevated inhibitory IkBα. Mutation studies indicate that suppression was partially dependent on the reactive thiol residue in S100A8, indicating effects in addition to those on ROS signaling. Inhibition by S100A8 may also be via increases in total neutral phosphatase and alkaline phosphatase activities that could reduce LPS-activated signaling.

S100A8 induced strong IL-10 expression in airway epithelial cells. Dexamethasone elevates S100A8 levels in lungs treated with LPS, with expression in alveolar macrophages and airway epithelial cells. Dexamethasone induced S100A8 mRNA in alveolar macrophagesand alveolar macrophages differentiated to the M2 type expressed S100A8.

Results support that proposal that S100A8 acts in concert with IL-10, and may contribute to some immunosuppressive functions mediated by corticosteroids.

Support: Funded by grants #630647 and #1027189, NHMRC Australia