SAA drives proinflammatory heterotypic macrophage differentiation in the lungviaCSF‐1R‐dependent signaling

Abstract

Serum amyloid A (SAA) is expressed locally in chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD), where macrophages that do not accord with the classic M1/M2 paradigm also accumulate. In this study, the role of SAA in regulating macrophage differentiation was investigated in vitro using human blood monocytes from healthy subjects and patients with COPD and in vivo using an airway SAA challenge model in BALB/c mice. Differentiation of human monocytes with SAA stimulated the proinflammatory monokines IL-6 and IL-1β concurrently with the M2 markers CD163 and IL-10. Furthermore, SAA-differentiated macrophages stimulated with lipopolysaccharide (LPS) expressed markedly higher levels of IL-6 and IL-1β. The ALX/FPR2 antagonist WRW4 reduced IL-6 and IL-1β expression but did not significantly inhibit phagocytic and efferocytic activity. In vivo, SAA administration induced the development of a CD11c(high)CD11b(high) macrophage population that generated higher levels of IL-6, IL-1β, and G-CSF following ex vivo LPS challenge. Blocking CSF-1R signaling effectively reduced the number of CD11c(high)CD11b(high) macrophages by 71% and also markedly inhibited neutrophilic inflammation by 80%. In conclusion, our findings suggest that SAA can promote a distinct CD11c(high)CD11b(high) macrophage phenotype, and targeting this population may provide a novel approach to treating chronic inflammatory conditions associated with persistent SAA expression.

IL-1β and Inflammasome Activity Link Inflammation to Abnormal Fetal Airway Development

“…Our data also suggest that IL-1β may function in a cell autonomous manner in fetal lung macrophages to accelerate the maturation process. Recent studies have reported similar mechanisms linking inflammatory mediators with macrophage differentiation in the lung (45, 46). In addition to cytokine effects on resident macrophages, recruitment of fetal monocytes into the developing lung may also lead to changes in lung innate immunity.…”

Highly Dynamic Transcriptional Signature of Distinct Macrophage Subsets during Sterile Inflammation, Resolution, and Tissue Repair

“…Ly6C pos macrophages entering the injured muscle highly expressed genes involved in inflammation, including acute-phase proteins, such as SAA3, S100A8/9, Lipocalin-2, and Haptoglobin (32). Both pathogen-associated and damageassociated molecular pattern molecules induce macrophage expression of S100A8 and S100A9 (33), which dimerize to form calprotectin, which, in turn, triggers SAA3 expression (34) by macrophages (35)(36)(37). Interestingly, macrophage-derived calprotectin is an early contributor of skeletal muscle myositis, which is characterized by a huge inflammatory infiltrate (38) and is also upregulated after exercise (39), suggesting that these macrophagederived proteins are crucial for launching the regeneration/remodeling process in skeletal muscle.…”

Aspirin-triggered resolvin D1 reduces pneumococcal lung infection and inflammation in a viral and bacterial coinfection pneumonia model

“…SAA is a potent chemotactic factor that mediates migration of leukocytes [14] and can also promote expression of proinflammatory mediators under in vitro [25] and in vivo conditions [12]. We have previously shown that SAA induces a proinflammatory macrophage phenotype [26] that stimulated acute neutrophilic lung inflammation in an Fpr2-dependent manner [16].…”

“…SAA is also a functional agonist for the formyl peptide receptor 2/lipoxin A 4 (LXA 4 ) receptor (Fpr2/ALX) where it stimulates leukocyte chemotaxis [14]. Furthermore, we have recently shown that local lung challenge with recombinant SAA potently stimulates neutrophilic inflammation via IL-17A-dependent mechanisms [15,16]. SAA can also promote neutrophil survival by suppressing the apoptotic machinery through activation of ERK and PI3K/Akt signaling pathways [17].…”