Neutrophil Homeostasis and Emergency Granulopoiesis: The Example of Systemic Juvenile Idiopathic Arthritis

Neutrophils are key pathogen exterminators of the innate immune system endowed with oxidative and non-oxidative defense mechanisms. More recently, a more complex role for neutrophils as decision shaping cells that instruct other leukocytes to fine-tune innate and adaptive immune responses has come into view. Under homeostatic conditions, neutrophils are short-lived cells that are continuously released from the bone marrow. Their development starts with undifferentiated hematopoietic stem cells that pass through different immature subtypes to eventually become fully equipped, mature neutrophils capable of launching fast and robust immune responses. During severe (systemic) inflammation, there is an increased need for neutrophils. The hematopoietic system rapidly adapts to this increased demand by switching from steady-state blood cell production to emergency granulopoiesis. During emergency granulopoiesis, the de novo production of neutrophils by the bone marrow and at extramedullary sites is augmented, while additional mature neutrophils are rapidly released from the marginated pools. Although neutrophils are indispensable for host protection against microorganisms, excessive activation causes tissue damage in neutrophil-rich diseases. Therefore, tight regulation of neutrophil homeostasis is imperative. In this review, we discuss the kinetics of neutrophil ontogenesis in homeostatic conditions and during emergency myelopoiesis and provide an overview of the different molecular players involved in this regulation. We substantiate this review with the example of an autoinflammatory disease, i.e. systemic juvenile idiopathic arthritis.

A zebrafish model of COVID-19-associated cytokine storm syndrome reveals differential proinflammatory activities of Spike proteins of SARS-CoV-2 variants of concern.

The sudden and unexpected appearance of the COVID-19 pandemic turned the whole world upside down in a very short time. One of the main challenges faced has been to understand COVID-19 patient heterogeneity, as a minority develop life-threatening hyperinflammation, the so-called cytokine storm syndrome (CSS). Using the unique advantages of the zebrafish model we report here the proinflammatory role of Spike (S) proteins from different SARS-CoV-2 variants of concern after injection into the hindbrain ventricle, a cavity filled with cerebrospinal fluid to which immune cells can be easily recruited and that mimics the alveolar environment of the human lung. We found that wild type/Wuhan variant S1 (S1WT) protein promoted neutrophil and macrophage recruitment, local and systemic hyperinflammation, emergency myelopoiesis, and hemorrhages. In addition, S1γ protein was more proinflammatory and S1δ was less proinflammatory than S1WT and, strikingly, Sβ promoted delayed and long-lasting inflammation. Pharmacological inhibition of the canonical inflammasome robustly alleviated S1 protein-induced inflammation and emergency myelopoiesis. In contrast, genetic inhibition of angiotensin-converting enzyme 2 strengthened the proinflammatory activity of S1, and the administration of angiopoietin (1-7) fully rescued S1-induced hyperinflammation and hemorrhages. These results shed light into the mechanisms orchestrating the COVID-19-associated CSS and the host immune response to different SARS-CoV-2 S protein variants.

Stromal inflammation is a targetable driver of hematopoietic aging

Hematopoietic aging is marked by a loss of regenerative capacity and skewed differentiation from hematopoietic stem cells (HSC) leading to impaired blood production. Signals from the bone marrow (BM) niche tailor blood production, but the contribution of the old niche to hematopoietic aging remains unclear. Here, we characterize the inflammatory milieu that drives both niche and hematopoietic remodeling. We find decreased numbers and functionality of osteoprogenitors (OPr) and expansion of pro-inflammatory perisinusoidal mesenchymal stromal cells (MSC) with deterioration of the sinusoidal vasculature, which together create a degraded and inflamed old BM niche. Niche inflammation, in turn, drives chronic activation of emergency myelopoiesis pathways in old HSCs and multipotent progenitors (MPP), which promotes myeloid differentiation at the expense of lymphoid and erythroid commitment and hinders hematopoietic regeneration. Remarkably, niche deterioration, HSC dysfunction and defective hematopoietic regeneration can all be ameliorated by blocking IL-1 signaling. Our results demonstrate that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during aging.

Landscape of Myeloid-derived Suppressor Cell in Tumor Immunotherapy

Myeloid-derived suppressor cells (MDSC) are a group of immature cells that produced by emergency myelopoiesis. Emerging evidences have identified the vital role of MDSC in cancer microenvironment, in which MDSC exerts both immunological and non-immunological activities to assist the progression of cancer. Advances in pre-clinical research have provided us the understanding of MDSC in cancer context from the perspective of molecular mechanism. In clinical scenario, MDSC and its subsets have been discovered to exist in peripheral blood and tumor site of patients from various types of cancers. In this review, we highlight the clinical value of MDSC in predicting prognosis of cancer patients and the responses of immunotherapies, therefore to propose the MDSC-inhibiting strategy in the scenario of cancer immunotherapies. Phenotypes and biological functions of MDSC in cancer microenvironment are comprehensively summarized to provide potential targets of MDSC-inhibiting strategy from the aspect of molecular mechanisms.

Characterization of low-density granulocytes in COVID-19

Severe COVID-19 is characterized by extensive pulmonary complications, to which host immune responses are believed to play a role. As the major arm of innate immunity, neutrophils are one of the first cells recruited to the site of infection where their excessive activation can contribute to lung pathology. Low-density granulocytes (LDGs) are circulating neutrophils, whose numbers increase in some autoimmune diseases and cancer, but are poorly characterized in acute viral infections. Using flow cytometry, we detected a significant increase of LDGs in the blood of acute COVID-19 patients, compared to healthy controls. Based on their surface marker expression, COVID-19-related LDGs exhibit four different populations, which display distinctive stages of granulocytic development and most likely reflect emergency myelopoiesis. Moreover, COVID-19 LDGs show a link with an elevated recruitment and activation of neutrophils. Functional assays demonstrated the immunosuppressive capacities of these cells, which might contribute to impaired lymphocyte responses during acute disease. Taken together, our data confirms a significant granulocyte activation during COVID-19 and suggests that granulocytes of lower density play a role in disease progression.

Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity–associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

Inflammatory signaling regulates hematopoietic stem and progenitor cell development and homeostasis

Inflammation exerts multiple effects on the early hematopoietic compartment. Best studied is the role of proinflammatory cytokines in activating adult hematopoietic stem and progenitor cells to dynamically replenish myeloid lineage cells in a process known as emergency myelopoiesis. However, it is increasingly appreciated that the same proinflammatory signaling pathways are used in diverse hematopoietic scenarios. This review focuses on inflammatory signaling in the emergence of the definitive hematopoietic compartment during embryonic life, and tonic inflammatory signals derived from commensal microbiota in shaping the adult hematopoietic compartment in the absence of pathogenic insults. Insights into the unique and shared aspects of inflammatory signaling that regulate hematopoietic stem and progenitor cell function across the lifespan and health span of an individual will enable better diagnostic and therapeutic approaches to hematopoietic dysregulation and malignancies.

Mouse multipotent progenitor 5 cells are located at the interphase between hematopoietic stem and progenitor cells

Hematopoietic stem cells (HSCs) and distinct multipotent progenitor populations (MPP1-4) contained within the Lin- Sca-1+ c-Kit+ (LSK) compartment have previously been identified using diverse surface marker panels. Here, we phenotypically define and functionally characterize MPP5 (LSK CD34+ CD135- CD48- CD150-). Upon transplantation, MPP5 support initial emergency myelopoiesis followed by stable contribution to the lymphoid lineage. Since MPP5 are capable of generating MPP1-4, but not HSCs, they represent a dynamic and versatile component of the MPP network. To characterize all hematopoietic stem and progenitor cells (HSPCs), we performed RNA-seq analysis to identify specific transcriptomic landscapes of HSCs and MPP1-5. This was complemented by single-cell (sc) RNA-seq analysis of LSK cells to establish the differentiation trajectories from HSCs to MPP1-5. In agreement with the functional reconstitution activity, MPP5 are located immediately downstream of HSCs but upstream of the more committed MPP2-4. This study provides a comprehensive analysis of the LSK compartment, focusing on the functional and molecular characteristics of the newly defined MPP5 subset.