NLRP3 knockout enhances immune infiltration and inflammatory responses and improves survival in a burn sepsis model.
NLRP3 knockout enhances immune infiltration and inflammatory responses and improves survival in a burn sepsis model.
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DOI：
10.1111/imm.13427
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发表时间：
2022-02
期刊：
影响因子：
6.4
通讯作者：
Jeschke MG
中科院分区：
文献类型：
--
作者：
Stanojcic M;Vinaik R;Abdullahi A;Chen P;Jeschke MG
虽然脓毒症是烧伤患者死亡的主要原因，但治疗并不总是有效的，潜在的机制尚未完全阐明。NLRP3炎性小体协调烧伤诱导的炎症驱动的病理生理过程。在这里，我们确定了NLRP3炎症小体激活对烧伤败血症细菌清除和死亡率的作用机制。我们获得了30只野生型和30只Nlrp3−/−小鼠的组织和血液。将小鼠置于25-30% TBSA烫伤后72小时的铜绿假单胞菌伤口感染的双击模型中。我们还获得了34例早期（烧伤后0-11天）和晚期（烧伤后≥12天）手术时间点的成人烧伤患者（≥18岁）和10名健康对照者的组织。小鼠研究表明，Nlrp3−/−能够提高30%的存活率和损伤部位的细菌清除率，并且与烧伤败血症野生型具有系统性相关。损伤部位和脂肪组织感染后（12小时），巨噬细胞和中性粒细胞的浸润急剧增加。急性期（24和72小时）后，淋巴器官和肝脏的巨噬细胞和中性粒细胞浸润增加。有趣的是，Nlrp3消融增加了急性全身炎症（IL-6, TNF-α, IL-1β）。脓毒性烧伤患者在急性期后脂肪NLRP3副产物的表达持续升高，这在迟发性脓毒症中更为明显。我们的研究结果表明，Nlrp3基因消融增强了急性组织特异性炎症反应性。很可能，这是通过增加急性免疫浸润和非持续性反应的炎症而矛盾地发生的。临床上，持续性nlrp3介导的炎症发生在脓毒性烧伤患者和正常烧伤患者中，并可能对患者的预后产生不利影响。
Although sepsis in burn patients is a major contributor to mortality, treatments are not always effective and underlying mechanisms have yet to be completely elucidated. NLRP3 inflammasome orchestrates burn-induced, inflammatory-driven pathophysiologic processes. Here, we determined the mechanism of NLRP3 inflammasome activation on bacterial clearance and mortality in burn sepsis. We obtained tissue and blood from 30 wild-type and 30 Nlrp3−/− mice. Mice were subjected to a two-hit model of 25–30% TBSA scald burn followed by Pseudomonas aeruginosa wound infection 72 hours after injury. We also obtained tissue from 34 adult burn patients (≥18 years of age) with early (0–11 days post-burn) and later (≥12 days post-burn) surgical time-points and ten healthy controls. Murine studies indicated that Nlrp3−/− had 30% improved survival and bacterial clearance at the site of injury and is systemically relative to burn sepsis wild type. Greater macrophage and neutrophil infiltration occurred acutely after infection (12 hours) to the site of injury and adipose tissue. This was followed by increased macrophage and neutrophil infiltration to lymphoid organs and liver beyond the acute phase (24 and 72 hours). Interestingly, Nlrp3 ablation increased acute systemic inflammation (IL-6, TNF-α, IL-1β). Septic burn patients had persistently increased adipose NLRP3 by-product expression beyond the acute phase that was more pronounced in late-onset sepsis. Our findings suggest that Nlrp3 genetic ablation enhanced acute tissue-specific inflammatory responsiveness. Likely, this occurs by paradoxically increasing acute immune infiltration and inflammation with a non-persistent response. Clinically, persistent NLRP3-mediated inflammation occurs in septic versus normal burn patients and potentially detrimentally impacts patient outcomes.
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DOI：
10.4049/jimmunol.1302752
发表时间：
2014-03-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gardner JC;Noel JG;Nikolaidis NM;Karns R;Aronow BJ;Ogle CK;McCormack FX
通讯作者：
McCormack FX
影响因子：
7
作者：
Barker BR;Taxman DJ;Ting JP
通讯作者：
Ting JP
影响因子：
32.4
作者：
Bronner DN;Abuaita BH;Chen X;Fitzgerald KA;Nuñez G;He Y;Yin XM;O'Riordan MX
通讯作者：
O'Riordan MX
影响因子：
5.3
作者：
Bogdanovic E;Kraus N;Patsouris D;Diao L;Wang V;Abdullahi A;Jeschke MG
通讯作者：
Jeschke MG
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J