Aged neutrophils contribute to the first line of defense in the acute inflammatory response

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Abstract

<p class="first" id="d16438665e200"> <b>Publisher's Note:</b> There is an <span class="generated">[Related article:]</span>Inside <i>Blood</i> Commentary on this article in this issue. </p><p id="d16438665e214"> <div class="list"> <a class="named-anchor" id="d16438665e216">  </a> <ul class="so-custom-list"> <li id="d16438665e217"> <div class="so-custom-list-content so-ol"> <p class="first" id="d16438665e218">Aged neutrophils exhibit a distinct, highly reactive phenotype that depends on age-related changes in their molecular repertoire. </p> </div> </li> <li id="d16438665e220"> <div class="so-custom-list-content so-ol"> <p class="first" id="d16438665e221">This specific phenotype of aged neutrophils enables them to serve as “first responders” in inflammatory reactions. </p> </div> </li> </ul> </div> </p><p class="first" id="d16438665e226">Under steady-state conditions, aged neutrophils are removed from the circulation in bone marrow, liver, and spleen, thereby maintaining myeloid cell homeostasis. The fate of these aged immune cells under inflammatory conditions, however, remains largely obscure. Here, we demonstrate that in the acute inflammatory response during endotoxemia, aged neutrophils cease returning to the bone marrow and instead rapidly migrate to the site of inflammation. Having arrived in inflamed tissue, aged neutrophils were found to exhibit a higher phagocytic activity as compared with the subsequently recruited nonaged neutrophils. This distinct behavior of aged neutrophils under inflammatory conditions is dependent on specific age-related changes in their molecular repertoire that enable these “experienced” immune cells to instantly translate inflammatory signals into immune responses. In particular, aged neutrophils engage Toll-like receptor-4- and p38 MAPK-dependent pathways to induce conformational changes in β2 integrins that allow these phagocytes to effectively accomplish their mission in the front line of the inflammatory response. Hence, ageing in the circulation might represent a critical process for neutrophils that enables these immune cells to properly unfold their functional properties for host defense. </p>

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Most cited references 22

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How leukocytes cross the vascular endothelium.

Dietmar Vestweber (2015)

Immune responses depend on the ability of leukocytes to move from the circulation into tissue. This is enabled by mechanisms that guide leukocytes to the right exit sites and allow them to cross the barrier of the blood vessel wall. This process is regulated by a concerted action between endothelial cells and leukocytes, whereby endothelial cells activate leukocytes and direct them to extravasation sites, and leukocytes in turn instruct endothelial cells to open a path for transmigration. This Review focuses on recently described mechanisms that control and open exit routes for leukocytes through the endothelial barrier.

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In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days.

Janesh Pillay, Ineke den Braber, Nienke Vrisekoop … (2010)

Neutrophils are essential effector cells of the innate immune response and are indispensable for host defense. Apart from their antimicrobial functions, neutrophils inform and shape subsequent immunity. This immune modulatory functionality might however be considered limited because of their generally accepted short lifespan (< 1 day). In contrast to the previously reported short lifespans acquired by ex vivo labeling or manipulation, we show that in vivo labeling in humans with the use of (2)H(2)O under homeostatic conditions showed an average circulatory neutrophil lifespan of 5.4 days. This lifespan is at least 10 times longer than previously reported and might lead to reappraisal of novel neutrophil functions in health and disease.

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Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence.

Coralie Martin, Peter C E Burdon, Gary Bridger … (2003)

In this study we provide evidence that the SDF-1alpha/CXCR4 chemokine axis is involved in both the retention of neutrophils within the bone marrow and the homing of senescent neutrophils back to the bone marrow. We show that the functional responses of freshly isolated human and murine neutrophils to CXCR2 chemokines are significantly attenuated by SDF-1alpha, acting via CXCR4. As a consequence, the mobilization of neutrophils from the bone marrow in vivo by the CXCR2-chemokine, KC, was dramatically enhanced by blocking the effects of endogenous SDF-1alpha using a specific CXCR4 antagonist. As neutrophils age, they upregulate expression of CXCR4 and acquire the ability to migrate toward SDF-1alpha. We show here that these senescent CXCR4(high) neutrophils preferentially home to the bone marrow in vivo in a CXCR4-dependent manner, suggesting a previously undefined mechanism for the clearance of senescent neutrophils from the circulation.