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    • propyl Despite this intriguing connection pre conditioning w

    2018-10-23

    Despite this intriguing connection, pre-conditioning with SL-LPS in the context of sepsis mortality has never been studied. Thus, we tested the propyl that SL-LPS pre-conditioning may exacerbate, instead of alleviate sepsis mortality in vivo. We employed the classical cecal ligation and puncture (CLP) model of polymicrobial sepsis, and examined mortality, tissue inflammation, and neutrophil bacterial killing in mice pre-conditioned with either low dose (50μg/kgbodyweight) or super-low dose (5ng/kgbodyweight) LPS. Another feature of this study involves the emerging concept of innate leukocyte programming. Although emerging studies reported the differential programming of monocytes/macrophages by SL-LPS and L-LPS (Morris et al., 2015), no data is available with regard to whether neutrophil, a key innate leukocyte in the context of sepsis, could be dynamically programmed by SL-LPS and L-LPS. Our study reveals that pre-conditioning with super-low dose LPS significantly increased CLP sepsis mortality and tissue inflammation, through reducing neutrophil NETosis and bacterial killing. Counter-intuitively, we observed that SL-LPS significantly suppressed ERK activation in neutrophils, instead of activating ERK. Taken together, our study reveals programming dynamics of innate immunity in vivo by SL-LPS.
    Materials and Methods
    Results
    Discussion Collectively, our current study provides a first systematic analysis of in vivo relevance of dynamic innate pre-conditioning in the context of sepsis (Fig. 7). Mortality risks for sepsis vary dramatically in humans, and patient conditions prior to septic insult may be a critical contributing factor. However, previous studies solely examined the potential beneficial effects of “tolerant” dose L-LPS in animal models of sepsis (Kopanakis et al., 2013; Landoni et al., 2012). These studies are consistent with in vitro mechanistic studies that tolerant dose L-LPS tempers the pro-inflammatory cytokine storm (Morris and Li, 2012). Intriguingly, recent studies in humans and mice reveal the presence of subclinical super-low dose SL-LPS in circulation, potentially responsible for non-resolving chronic inflammation (Sunil et al., 2007; Terawaki et al., 2010). We and others reported that innate leukocytes can be dynamically pre-conditioned to opposite functional states in vitro, with super-low dose LPS selectively “primes” the expression of pro-inflammatory cytokines (Deng et al., 2013; Zhang and Morrison, 1993b). Our data provide much-needed evidence to support the pathological relevance of super-low dose endotoxemia, and extend the intriguing dynamics of innate priming and tolerance to an in vivo model of sepsis. Emerging in vitro studies reveal that innate monocytes may adopt distinct phenotypes by prior conditioning or “training” with varying dosages of innate stimulants (Deng et al., 2013; Netea et al., 2011; Quintin et al., 2012). For example, pre-conditioning with super-low dose LPS “primes” the expression of selected pro-inflammatory mediators such as TNF-α and IL-12, while suppressing the expression of iNOS (Hirohashi and Morrison, 1996). In contrast, pre-conditioning with elevated low dose LPS “tolerizes” the expression of selected genes (Hirohashi and Morrison, 1996). In consistent with these in vitro studies, we confirmed the “priming” and “tolerance” effects in vivo, and demonstrated that pre-conditioning with super-low dose LPS exacerbates the levels of TNF-α and KC in CLP-mice. Studies also suggest that the innate responses to varying dosages of LPS may not fit into the simple paradigm of priming and tolerance, and hint at more complex adaptation profiles (Foster et al., 2007). On a separate note, the adaptation phenomenon to varying dosages of LPS is different as compared to the traditional M1/M2 concept, in which distinct agonists are required for the differential activation of M1 (by IFNγ) or M2 (through IL-4) (Martinez et al., 2008). Similar adaptation paradigm to varying signal strength may also exists in other immune cell types. For instance, although T helper cells are well known to adopt different functional states (Th1, Th2, Th17, Treg) when challenged with distinct combination of cytokines (Hong et al., 2011), emerging recent study reported that T helper cell differentiation can also be achieved through varying the signal strength of the TCR signal (Salmond et al., 2014; van Panhuys et al., 2014). Collectively, these studies draw serious attention to the issue of dynamic responses of immune cells when challenged with varying dosages of the same stimulant.