LJI researchers gain new understanding of how neutrophils

As an arm of the innate immune system, white blood cells called neutrophils form the first line of defense against invading pathogens. Neutrophils spend most of their lives racing through the bloodstream, patrolling for bacteria or other foreign particles. Once they arrive at tissues besieged by infectious agents, they halt on a dime and then blast through the vessel wall to reach the inflammatory attack site. They do this by activating integrins, a class of adhesion receptors that can switch on in less than a second.



Now, a paper published by La Jolla Institute for Allergy and Immunology (LJI) researchers reveals an entirely unanticipated way in which neutrophil receptors grab onto a capillary wall in preparation to breach it, as well as a cute trick they use to keep cells from sticking to each other or busting through the wrong place.



“Once neutrophils sense a site of infection behind a capillary wall, they need to get out of circulation fast. Previously, we knew they initiated that by switching on adhesion molecules to grab onto a vessel in less than a second,”


“In our new study we have discovered an unexpected way that these molecules change their shape to do that.”



Many researchers thought that integrin receptors protruding from neutrophils became adherent via a “switchblade” mechanism. In it, resting integrins on neutrophils moving through the blood remain bent and minimally sticky until cells rolled over a region of infection. There, integrins underwent two sequential shape changes–step one always preceding step two–such that the bent head of the protein sprung open rapidly, exposing a hidden adhesive patch that glommed onto a protein in the vessel wall called ICAM-1.



The new study reveals the knife to be more complex. Combining high resolution microscopy called quantitative dynamic footprinting with methods to track human neutrophils rolling across an artificial surface coated with ICAM-1 and other signaling factors, Ley’s team observed that some neutrophil clusters did in fact exhibit integrins undergoing the conventional two-step activation mechanism.

「新しい研究はそのナイフがもっと複雑な事を明かしています。定量動的フットプリンティングと呼ばれる高分解能顕微鏡と ICAM-1と他の信号伝達因子でコーティングされている、人工表面を転がっているヒト好中球を追跡するための方法を組み合わせることで、Leyのチームは一部の好中球集団が、従来式の2段階活性化機構を経験する事で、インテグリンを実際に発現していることを観測しました。」

In other clusters, however, integrins assumed an unorthodox shape, one that exposed the high affinity patch but managed to hold the receptor in a bent conformation, as if step two had occurred prior to step one. Time-lapse analysis revealed that either cluster type eventually gave rise to fully activated, adherent integrins (with their blade fully sprung). There simply seemed to be two ways to spring it.



Cis-trans interactions

The study’s blockbuster finding revealed what that mysterious sticky patch was doing in peculiar clusters of bent integrins. Discovering this required a different technique called FRET, often applied to measure distances between two molecules at nanometer resolution.


That approach revealed that sticky patches in bent integrins were actually touching and binding to adjacent ICAM-1 proteins embedded in membrane of the very same cell, an interaction biologists call in cis. That contact locked the integrin receptor into off-mode, preventing it from binding to ICAM-1 expressed “across the way” on blood vessel cells, intercellular interactions biologists describe as in trans.

「そのアプローチは、屈曲(休眠状態の)インテグリン中の粘着性パッチが、生物学者が、in cisと呼ぶ相互作用である、全く同じ細胞の皮膜内に埋まっている隣接したICAM-1タンパク質に、実際に接していて結合している事を明らかにしました。その接触は、インテグリン受容体をオフモードに固定して、生物学者がin transとして表現している細胞間相互作用である、血管細胞の反対側に発現するICAM-1と結合するのを防いでいます。」

in cis, in transと呼ばれる相互作用について少し調べてみました。

Cis-trans interactions of cell surface receptors: biological roles and structural basis

Cell surface receptors bind ligands expressed on other cells (in trans) in order to communicate with neighboring cells. However, an increasing number of cell surface receptors are found to also interact with ligands expressed on the same cell (in cis).

「細胞表面受容体は、隣接する細胞と交信するために、別の細胞(in trans)上に発現するリガンドを結合します。しかし、同じ細胞(in cis)上に発現するリガンドを使って、同様に情報のやり取りをしている、ますます多くの細胞表面受容体が見つかっています。」

同じ細胞上に発現するリガンドとの相互作用がin cisで、別の細胞上に発現するリガンドとの相互作用がin transということのようですが、はっきりした事はよく分かりません。

Or, as new textbooks may say: High affinity in cis binding of neutrophil integrins to adjacent ICAM-1 molecules in the same membrane serves as an auto-inhibitory mechanism to block integrin engagement in trans with ICAM-1 expressed on cells in vessel walls, inhibiting adhesion and blocking an inflammatory response.

「あるいは、新しいテキストが、同じ細胞膜中に隣接するICAM-1分子と好中球インテグリンのin cis結合の高親和性が、血管壁中の細胞上に発現するICAM-1とin transインテグリン関与を阻害するための自己抑制メカニズムとしての役目を果たしていて、粘着を阻害して炎症反応をブロックしています、と書くかもしれません。」

同じ細胞上に発現するICAM-1とインテグリンがin cis結合して、その結合の高親和性が、血管壁細胞に発現するICAM-1と好中球インテグリンがin trans結合するのを防いでいて、その結果として、粘着性が阻害されて炎症反応を抑え込むことが可能なようです。

The discovery that integrins restrain themselves like this has profound consequences for inflammatory disease. Monoclonal antibodies developed to specifically block interactions of neutrophil integrins with vessel wall proteins are already approved to treat coronary artery disease, autoimmune inflammatory bowel disease and multiple sclerosis.


好中球インテグリンの自己抑制メカニズムをキープしてin trans結合を阻害することで、炎症を抑制する薬や、逆にこの自己制御モードをオフにする事で、好中球を戦闘モードにする事も可能になるそうです。かなり画期的な発見であることは確かなようです。健康を守る免疫系細胞が健康を害したり、人間の体というのは本当に不思議なもんです。