S100A8 Induces IL-10 and Protects against Acute Lung Injury

Abstract

S100A8 is considered proinflammatory by activating TLR4 and/or the receptor for advanced glycation end products. The aim was to investigate inflammatory effects of S100A8 in murine lung. S100A8 was administered to BALB/c mice by nasal inhalation and genes induced over a time-course assessed. LPS was introduced intranasally either alone or 2 h after pretreatment of mice with intranasal application of S100A8 or dexamethasone. A Cys42-Ala42 mutant S100A8 mutant was used to assess whether S100A8’s effects were via pathways that were dependent on reactive oxygen species. S100A8 induced IL-10 mRNA, and expression was apparent only in airway epithelial cells. Importantly, it suppressed acute lung injury provoked by LPS inhalation by suppressing mast-cell activation and induction of mediators orchestrating leukocyte recruitment, possibly by reducing NF-κB activation via an IκBα/Akt pathway and by downmodulating pathways generating oxidative stress. The Cys42-Ala42 S100A8 mutant did not induce IL-10 and was less immunosuppressive, indicating modulation by scavenging oxidants. S100A8 inhibition of LPS-mediated injury was as potent, and outcomes were remarkably similar to immunosuppression by dexamethasone. We challenge the notion that S100A8 is an agonist for TLR4 or the receptor for advanced glycation end products. S100A8 induced IL-10 in vivo and initiates a feedback loop that attenuates acute lung injury.

S100A8 and S100A9 proteins are expressed by human corneal stromal dendritic cells

“…Moreover, A8 and A9 expression levels are strongly enhanced by glucocorticosteroids, and mechanisms for their gene induction strongly support immunomodulatory roles 9. Furthermore, in the lung, A8 strongly induces IL-10 in airway epithelial cells, indicating an important feedback loop8 that could potentially influence DC cell functions. Alternatively, as in atherosclerosis24 one DC population may originate from a monocyte precursor that is likely to express A8 and A9, and another may mature/differentiate from a precursor of different origin that does not express the S100s.…”

“…S100A8 (A8) and S100A9 (A9) are constitutively expressed in myeloid-derived cells including neutrophils and monocytes, and are induced in macrophages,8 capillary endothelial and epithelial cells by Toll-like receptor agonists 7. These proteins promote pro-inflammatory7 and immunoprotective responses,8 9 and are linked to antioxidant defence 10. The A8/A9 complex,7 also known as calprotectin, can suppress acute inflammation11 and has antimicrobial activities 12.…”

Effect of Hangeshashinto on calprotectin expression in human oral epithelial cells

“…Calprotectin level in body fluids, skin and feces is elevated in some inflammatory diseases including ulcerative colitis, inflammatory arthritis, cystic fibrosis, cardiovascular disease and periodontitis [16][17][18][19][20][21]. Furthermore, S100A8, a component of calprotectin, shows anti-inflammatory properties by immunosuppressive actions in lung inflammation and protects against acute injury caused by endotoxin [22]. These findings suggest that calprotectin prevents infectious diseases such as periodontal diseases and maintains the health of the oral cavity.…”

Termination of Immune Activation: An Essential Component of Healthy Host Immune Responses

“…In recent years, a number of mediators that may bridge the immune termination events and subsequent resolution and/or repair of inflammation have been identified [92,93,94,95,96,97,98,99]. These include a new class of pro-resolution lipid mediators, such as arachidonic acid-derived lipoxins, ω-3 polyunsaturated fatty acid-derived resolvins, protectins, and maresins [93,94].…”

“…Pro-resolutions lipids may exhibit both pro-inflammatory and pro-resolution properties [95] allowing effective but well-regulated inflammatory responses and measured tissue repair that limits extensive fibrosis. Although the list is far from comprehensive, other pro-resolution or dual-effect mediators that regulate pro-resolving molecular and cellular circuits are several micro-RNAs [96], annexins [97], nitric oxide [98] and members of the S100 proteins [99]. …”