FIGURE 3.

Schematic role of SP-C in pulmonary metaflammation. (Left panel) comparison between the status of AE1C in the presence (healthy alveolus, top panel) or absence (damaged alveolus, bottom panel) of SP-C. (Right panel: 1) Priming signal: TLR4 signaling is abrogated under the presence of mature SP-C. On the one hand, SP-C interferes with the complex formation of LBP and CD14 potentially attenuating TLR4 mediated NLPR3 priming in response DAMP/PAMP stimuli. This ant-inflammatory effect may be further potentiated by the N-terminal segment of SP-C transferring TLR4 activators either into neighboring phospholipid microsomes or directly to the cytoplasmic compartment of the macrophage (Chaby et al., 2005; Garcia-Verdugo et al., 2009). Moreover, maintained surfactant homoeostasis/surfactant catabolism counteracts the accumulation/formation of oxidized lipid species and cholesterol clefts on the one hand, and minimizes atelec- and volutrauma on the other hand (Ruwisch et al., 2020), likely diminishing the release of DAMPS like ATP on the other hand. Together this prevents the buildup of inflammasome oligomerizing stimuli, what may at least partly explain the aberrant inflammatory response of SP-C KO mice to various inflammatory stimuli in contrast to WT mice (Glasser et al., 2008, 2013a). (Right panel: 2) Activating signal: NLRP3 inflammasome comprises an initial NFκβ related priming phase, preceding a secondary activation signal (Swanson et al., 2019): In the first step various proinflammatory DAMPS (oxysterols, oxidized PL species) or PAMPS (LPS) activate macrophages via TLR-4 signaling via an either LPS binding protein (LBP)/CD14 dependent or independent way (Chaby et al., 2005; Garcia-Verdugo et al., 2009). Thereby, LBP facilitates the binding of e.g., LPS to CD14, what accelerates LPS related TLR4 signaling. TLR4 signaling in turn drives NFκB-mediated expression of NLRP3, pro-IL-β1 and proIL-18 (Priming phase) (Gasse et al., 2007; Swanson et al., 2019). In the second step, multiple potential hits including PAMPS like extracellular ATP (Mariathasan et al., 2006; Swanson et al., 2019), intracellular cholesterol clefts (Ertunc and Hotamisligil, 2016), oxysterols and oxidized phospholipid derived mitochondrial oxidative stress (Fessler, 2017; Manon et al., 2018) induce previously synthetized NLRP3 to form oligomers with caspase 1 and ASC leading to mature inflammasome formation. Thereby, increased level of extracellular ATP may be derived from mechanically stressed AEC1 (Hasan et al., 2017), leading to an inflammasome activating K⁺ efflux via P2X7R. Meanwhile, SP-C deficiency related dysfunctional surfactant catabolism and surfactant dysfunction may favor the generation of oxidized PL species and the formation of cholesterol clefts (Fessler and Summer, 2016; Ruwisch et al., 2020). Likewise, these cholesterol crystals cause lysosomal stress, which in turn resembles another potent driving factor of inflammasome formation via induction of a K⁺ efflux. Finally, the active NLRP3 inflammasome converts inactive proIL-1β and proIL-18 into their active form IL-1β and IL-18. IL-1β promotes fibrotic remodeling (Gasse et al., 2007; Cassel et al., 2008; Wree et al., 2014; Lv et al., 2018). Meanwhile, another effect of accumulation of injurious lipid species inside the macrophages may also prime their hosts toward a profibrotic aaAM-phenotype (Romero et al., 2014) via induction of several aaAM related genes including, chitinase-like-3 (YM1), which has also been described to form electron dense crystals in various alternative activation of macrophages-disease models (Hoenerhoff et al., 2006; Mora et al., 2006), what may result in a profibrotic feed-forward loop (Smigiel and Parks, 2018).