S100A8/A9 Drives Neuroinflammatory Priming and Protects against Anxiety-like Behavior after Sepsis

Abstract

Sepsis commonly results in acute and chronic brain dysfunction, which dramatically increases the morbidity associated with this common disease. Chronic brain dysfunction in animal models of sepsis survival is linked to persistent neuroinflammation and expression of multiple cytokines. However, we have found previously that microglia predominantly upregulate the damage associated molecule S100A8/A9 after sepsis. In this article, we show that S100A8/A9 is increased in the brains of patients who died of sepsis and that S100A8 is expressed in astrocytes and myeloid cells. Using a mouse model of sepsis survival, we show that S100A8/A9 is persistently expressed in the brain after sepsis. expression is necessary for recruitment of neutrophils to the brain and for priming production of reactive oxygen species and TNF-α secretion in microglia and macrophages. However, despite improving these indices of chronic inflammation, deficiency results in worsened anxiety-like behavior 2 wk after sepsis. Taken together, these results indicate that S100A8/A9 contributes to several facets of neuroinflammation in sepsis survivor mice, including granulocyte recruitment and priming of microglial-reactive oxygen species and cytokine production, and that these processes may be protective against anxiety behavior in sepsis survivors.

Single‐cell deconstruction of post‐sepsis skeletal muscle and adipose tissue microenvironments

“…On a transcript level, common themes among DEGs across cell types/tissues were response to infection and tissue damage. Examples include (i) S100a8, S100a9, and Retnlg in brain 34,35 ; (ii) Lcn2 in brain and liver 35,36 ; (iii) Mt1 and Mt2 in macrophages, liver, kidney, ovary, lung, uterus, brain, pancreas, heart, spleen, and intestine [37][38][39][40] ; (iv) Ifitm3 in T-memory cells in brain and lung 41,42 ; (v) Ngp in brain and lung 35,43 ; and (vi) Saa3 in lung and epithelial cells. 44,45 Notably, one striking finding from our study was the significant upregulation of S100a8/9, Saa3, and Lcn2 across multiple cell types in both muscle and fat ( Figure 3A and Supporting Information, Figures S17 and S18).…”

Necrotizing enterocolitis is associated with acute brain responses in preterm pigs

“…These proteins form homodimers (Calgranulins) and a heterocomplex (Calprotectin) and are shown to interact and regulate the biological activities of receptors for advanced glycation end products (RAGE) and TLR4 (gram-negative bacterial liposaccharide receptor). Although S100A8 and S100A9 were upregulated within the CNS in response to different pathological conditions [ 66 , 67 ], their role in brain development is poorly understood. We now first show that the extra-cellular application of S100A9 or S100A8/A9 (but not S100A8 alone) dose-dependently promotes neurite outgrowth from primary hippocampal neurons, further pointing to the stimulatory effect of inflammatory factors on neuronal plasticity.…”

Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation

“…The cause of these complications remains unclear, though persistent inflammation and primed immune responses have been hypothesized to contribute. Murine CLP models have demonstrated enhanced TNFα production in splenic inflammatory monocytes and brain microglia for at least 2 weeks after sepsis ( 38 , 39 ) suggesting a possible link between primed cells and long-term organ dysfunction. Meanwhile, persistent inflammation may influence patient outcome, as observations of persistent elevation of IL-6 in patients with pneumonia have been associated with increased risk for long-term mortality due to cardiovascular disease or renal failure ( 40 ).…”