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C-type lectin receptor Dectin-1 regulates the balance of mouse intestinal microbiota

神谷, 知憲 東京大学 DOI:10.15083/0002001697

2021.09.08

概要

【研究背景と目的】
腸管にはウィルスや真菌、細菌などの無数の生物が共生しており、宿主と相互に作用し共生している。これら共生生物は宿主の免疫システムと密接な関係にあり、お互いを制御している。近年、腸内に共生する細菌の働きが注目されており、腸管のみならず全身性に影響があるという報告もある。このことから、腸内細菌叢を含む腸管恒常性の破綻は身体に重篤な影響をもたらし、様々な疾患の発病につながっている。腸内菌叢バランスの破綻、即ちDysbiosisを防ぐシステムが幾つか存在する中で、近年の研究により、粘膜免疫系、とりわけ自然免疫受容体がそれらに対しての制御機構の一つとして解析が進められ、その役割が期待されている。

Dectin-1は自然免疫受容体の一種であるC型レクチン受容体ファミリー分子の一つである。Dectin-1はβ-glucanの受容体であり、細胞内領域にITAM(Immunoreceptor Tyrosine-based Activation Motif)を有する。ITAMによって最終的にNF-κB誘導され、炎症性サイトカイン、別の経路から活性酸素が誘導されることで、真菌感染に対して防御的に働くことが知られている。また、古くからβ-glucanは酵母やキノコから多く摂取され、一部の健康食品として販売され、腸や身体に有益な効果をもたらすことが知られている一方で、β-glucanが腸管免疫系の活性化に働くことが最新の研究により報告されている。しかし、β-glucan、またはDectin-1の腸管恒常性、腸管免疫系への効果のメカニズムは未だ解明されていない。本研究ではDectin-1を介したβ−glucanの腸管恒常性維持を制御するメカニズムについて解析を行った。

【結果と考察】
Dectin-1欠損マウスでの腸内細菌叢、及び腸管免疫系の変化
Dectin-1の大腸免疫細胞上での発現を解析した結果、骨髄由来の細胞に発現していることが確認された。そして、Dectin-1の欠損マウスを用いることにより、Dectin-1の腸管免疫系での働きを確認した。デキストラン硫酸ナトリウム(DSS)により大腸炎を誘導した結果、野生型マウスに比べDectin-1欠損マウスでは大腸炎が抑制され、炎症を抑制する制御性T細胞がDectin-1欠損マウスにて増加していることが明らかとなった。制御性T細胞増殖の原因を解明するため、腸管免疫系に影響を及ぼすことが報告されていることから、腸内細菌叢の同定を試みた。糞便中の16SrDNAを次世代シーケンサーにより解析した結果、Dectin-1欠損マウスの糞便中ではLactobacillus murinus14221株(L. murinus)の大幅な増加が確認された。この菌株を無菌マウスにノトバイオードすると、大腸粘膜固有層にて制御性T細胞が増加していた。これらの結果から、Dectin-1欠損マウスにて増殖したL. murinusが抑制性T細胞を誘導し、腸炎を抑制することが明らかとなった。

L. murinus制御メカニズム
次にDectin-1がどのようにL. murinusを制御しているかを解析した。上皮細胞から産生される抗菌タンパクの発現に着目し、Dectin-1欠損マウスの大腸上皮細胞に発現する抗菌タンパクを測定した結果、抗菌ペプチドS100A8遺伝子の発現量が減少していることがわかった。そして、S100A8はS100A9とヘテロダイマー形成することで抗菌活性を示し、L. murinusの増殖を抑制することがinvitroの試験により明らかとなった。Dectin-1の下流では種々のサイトカインの産生が知られていることから、腸管におけるDectin-1発現細胞へリガンドであるβ-glucanの刺激を加えると、IL-17Fを誘導することが明らかとなった。さらに、IL-17FはDectin-1の粘膜固有層にて発現量、及び産生量が低下していることが確認された。

そして、種々のサイトカインがS100A8を誘導するという報告から、invitro試験における腸管上皮細胞への抗菌タンパク誘導確認試験を実施した。結果、IL-22、IL-23、そしてIL-17Fが大腸上皮細胞の初代培養試験にてS100A8の発現を誘導した。さらに、IL-17Fを欠損させたマウスでは大腸上皮細胞におけるS100A8の発現が低下し、糞便中のL. murinusの存在量が増加していることが明らかとなった。Dectin-1、IL-17F、S100A8の関係性を示す実験として、腸管骨髄由来細胞をβ-glucanで刺激し、その培養上清と大腸上皮細胞とをさらに共培養しS100A8の発現を測定した。結果、Dectin-1、及びIL-17F欠損マウス由来の腸管骨髄由来細胞ではS100A8の発現が低下していた。これらのことから、腸管骨髄由来細胞に発現するDectin-1を介してIL-17Fの産生が誘導され、大腸上皮細胞のS100A8の産生が促進される。そしてS100A8/S100A9によりL. murinusの増殖が制御されていることが明らかとなった。この結果はC型レクチン受容体による腸内細菌叢制御機構を初めて明らかにするものであり、腸管恒常性維持システムの解明に繋がるものと推察される。

経口摂取β-glucanによる腸管恒常性維持機構
腸管には様々な物質や生物由来のβ-glucanが存在する。Dectin-1が腸管免疫系制御に働くことから、β-glucanの由来を探索することで、寄与が高いβ-glucanを調整することで腸管恒常性を制御する可能性を期待した。β-glucan合成酵素を有する細菌や腸内細菌が存在することから、その細胞壁表面をβ-glucan認識タンパクにて標識したが、いずれもβ-glucanを検出することはできず、また無菌マウスと通常飼育マウスのS100A8発現細胞に違いがないことから、細菌由来のβ-glucanはこの制御機構に働かないことが判明した。通常マウス飼料には酵母が多量に含まれており、これはヒトがパンやキノコを食しβ-glucanを経口摂取することと同義である。そこで、食物に含まれるβ-glucanについて検討するため、β-glucanを含まない飼料にてマウスを育成した。その結果、S100A8の発現低下、L. murinusの増加、さらにDectin-1欠損マウスと同様にDSS誘導大腸炎が抑制されることが明らかとなった。

上記の結果を総合し、経口摂取されたβ-glucanは腸管骨髄由来細胞に発現するDectin-1を介してIL-17Fを誘導し、大腸上皮細胞のS100A8の産生を促すことが示された。そして、S100A8/S100A9によりL. murinusの増殖が制御され、Dectin-1欠損マウスでは制御性T細胞が増殖し大腸炎を抑制することが明らかとなった。経口摂取されるβ-glucanを制御することで、腸管恒常性を維持できるメカニズムが明らかとなった。これは食物による免疫システムの制御メカニズムを示唆するものであり、食品による健康増進が証明された。

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