A Soluble Form of LMIR5/CD300b Amplifies Lipopolysaccharide-Induced Lethal Inflammation in Sepsis
A Soluble Form of LMIR5/CD300b Amplifies Lipopolysaccharide-Induced Lethal Inflammation in Sepsis
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DOI：
10.4049/jimmunol.1201139
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发表时间：
2012-07
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通讯作者：
Y. Yamanishi;Mariko Takahashi;Kumi Izawa;Masamichi Isobe;S. Ito;Akiho Tsuchiya;Akie Maehara;Ayako Kaitani;Tomoyuki Uchida;K. Togami;Y. Enomoto;F. Nakahara;T. Oki;M. Kajikawa;H. Kurihara;T. Kitamura;J. Kitaura
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作者：
Y. Yamanishi;Mariko Takahashi;Kumi Izawa;Masamichi Isobe;S. Ito;Akiho Tsuchiya;Akie Maehara;Ayako Kaitani;Tomoyuki Uchida;K. Togami;Y. Enomoto;F. Nakahara;T. Oki;M. Kajikawa;H. Kurihara;T. Kitamura;J. Kitaura
白细胞单免疫球蛋白样受体5(LMIR5，又称CD300b)是一种表达于髓系细胞的激活型受体。我们先前已经证明T细胞Ig粘蛋白1在小鼠肾脏缺血再灌注损伤中作为LMIR5的配体发挥作用。在这篇文章中，我们证明了LMIR5与内毒素诱导的小鼠脓毒症有关。值得注意的是，中性粒细胞通过蛋白水解性裂解表面LMIR5，结构性地释放出可溶性形式的LMIR5(SLMIR5)。用TLR激动剂刺激可增加sLMIR5的释放。脂多糖给药或腹膜炎诱导的小鼠血清sLMIR5水平增加，这一水平实质上被中性粒细胞耗尽所抑制。因此，中性粒细胞是体内脂多糖诱导sLMIR5的主要来源。另一方面，IP。给予sLMIR5的替代品LMIR5-Fc与常驻巨噬细胞(Mϕ)结合并刺激小鼠的一过性炎症。LMIR5-Fc通过其未知的配体在体外诱导腹膜Mϕ产生细胞因子。有趣的是，LMIR5缺乏显著降低了脂多糖注射的小鼠全身细胞因子的产生和脓毒症的死亡率，尽管它不影响脂多糖刺激的腹膜Mϕ体外细胞因子的产生。重要的是，LMIR5-Fc降低了LMIR5基因缺陷小鼠对内毒素或腹膜炎诱导的脓毒症死亡的抵抗力，暗示sLMIR5参与了体内的内毒素反应。总的来说，中性粒细胞衍生的sLMIR5放大了内毒素诱导的致命性炎症。
Leukocyte mono-Ig–like receptor 5 (LMIR5, also called CD300b) is an activating receptor expressed in myeloid cells. We have previously demonstrated that T cell Ig mucin 1 works as a ligand for LMIR5 in mouse ischemia/reperfusion injury of the kidneys. In this article, we show that LMIR5 is implicated in LPS-induced sepsis in mice. Notably, neutrophils constitutively released a soluble form of LMIR5 (sLMIR5) through proteolytic cleavage of surface LMIR5. Stimulation with TLR agonists augmented the release of sLMIR5. LPS administration or peritonitis induction increased serum levels of sLMIR5 in mice, which was substantially inhibited by neutrophil depletion. Thus, neutrophils were the main source of LPS-induced sLMIR5 in vivo. On the other hand, i.p. administration of LMIR5-Fc, a surrogate of sLMIR5, bound to resident macrophages (Mϕ) and stimulated transient inflammation in mice. Consistently, LMIR5-Fc induced in vitro cytokine production of peritoneal Mϕ via its unknown ligand. Interestingly, LMIR5 deficiency profoundly reduced systemic cytokine production and septic mortality in LPS-administered mice, although it did not affect in vitro cytokine production of LPS-stimulated peritoneal Mϕ. Importantly, the resistance of LMIR5-deficient mice to LPS- or peritonitis-induced septic death was decreased by LMIR5-Fc administration, implicating sLMIR5 in LPS responses in vivo. Collectively, neutrophil-derived sLMIR5 amplifies LPS-induced lethal inflammation.