S100A9 Induced Inflammatory Responses Are Mediated by Distinct Damage Associated Molecular Patterns (DAMP) Receptors In Vitro and In Vivo

Abstract

Release of endogenous damage associated molecular patterns (DAMPs), including members of the S100 family, are associated with infection, cellular stress, tissue damage and cancer. The extracellular functions of this family of calcium binding proteins, particularly S100A8, S100A9 and S100A12, are being delineated. They appear to mediate their functions via receptor for advanced glycation endproducts (RAGE) or TLR4, but there remains considerable uncertainty over the relative physiological roles of these DAMPs and their pattern recognition receptors. In this study, we surveyed the capacity of S100 proteins to induce proinflammatory cytokines and cell migration, and the contribution RAGE and TLR4 to mediate these responses in vitro. Using adenoviral delivery of murine S100A9, we also examined the potential for S100A9 homodimers to trigger lung inflammation in vivo. S100A8, S100A9 and S100A12, but not the S100A8/A9 heterodimer, induced modest levels of TLR4-mediated cytokine production from human PBMC. In contrast, for most S100s including S100A9, RAGE blockade inhibited S100-mediated cell migration of THP1 cells and major leukocyte populations, whereas TLR4-blockade had no effect. Intranasal administration of murine S100A9 adenovirus induced a specific, time-dependent predominately macrophage infiltration that coincided with elevated S100A9 levels and proinflammatory cytokines in the BAL fluid. Inflammatory cytokines were markedly ablated in the TLR4-defective mice, but unexpectedly the loss of TLR4 signaling or RAGE-deficiency did not appreciably impact the S100A9-mediated lung pathology or the inflammatory cell infiltrate in the alveolar space. These data demonstrate that physiological levels of S100A9 homodimers can trigger an inflammatory response in vivo, and despite the capacity of RAGE and TLR4 blockade to inhibit responses in vitro, the response is predominately independent of both these receptors.

Topical application of the anti-microbial chemical triclosan induces immunomodulatory responses through the S100A8/A9-TLR4 pathway

“…Other pathways may also be activated. S100A9-induced airway inflammation in mice for example, was reported to occur independent of both RAGE and TLR4 signaling (Chen et al 2015). Thus, the roles for the S100A8/A9-TLR4 axis in the modulation of immune responses are still not fully understood.…”

S100A8 and S100A9 Secreted by Allergens in Monocytes Inhibit Spontaneous Apoptosis of Normal and Asthmatic Neutrophils via the Lyn/Akt/ERK Pathway

“…S100A8 and S100A9 belong to the S100 family proteins and are constitutively expressed in monocytes and neutrophils [9][10][11]. They play as damage-associated molecular pattern (DAMP) via Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (RAGE), and triggers the pathogenesis of asthma, chronic obstructive pulmonary disease, colitis, rheumatoid arthritis, Alzheimer's disease, and tumor [12,13]. Our reports recently demonstrated that S100A8 and S100A9 induce cytokine secretion, which is involved in regulation of neutrophil apoptosis [14,15].…”

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

“…It also belongs to the family of damage-associated molecular patterns (DAMPs). Studies have shown that S100A8 plays an important role in regulating tissue inflammation as a ligand of toll-like receptor 4 (TLR4) and/or receptor for advanced glycation end products (RAGE) (7,8). Aberrant expression of S100A8 has been found in different types of tumors including CRC (9) and the accumulation of S100A8 positive cells is always located in the invasive margin of colorectal carcinoma (10) which plays a critical role in the tumor microenvironment.…”