Neutrophils in rheumatoid arthritis: More than simple final effectors (2022)

Table of Contents
Autoimmunity Reviews Abstract Introduction Section snippets Immune mediators production Conclusion Take-home messages Acknowledgments References (40) Am J Pathol Int J Biochem Cell Biol FEBS Lett J Autoimmun J Autoimmun Cell Immunol J Autoimmun Autoimmun Rev Blood Neutrophils and immunity: challenges and opportunities Nat Rev Immunol Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing Nat Med Secretion of oncostatin M by neutrophils in rheumatoid arthritis Arthritis Rheum Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis Arthritis Res Ther Expression of vascular endothelial growth factor by synovial fluid neutrophils in rheumatoid arthritis (RA) Clin Exp Immunol Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases Arthritis Rheum Tumor necrosis factor alpha activates release of B lymphocyte stimulator by neutrophils infiltrating the rheumatoid joint Arthritis Rheum Citrullination of synovial proteins in murine models of rheumatoid arthritis Arthritis Rheum Granulocyte colony-stimulating factor and neutrophils—forgotten mediators of inflammatory disease Nat Clin Pract Rheumatol Phagocyte-derived reactive oxygen species as suppressors of inflammatory disease Arthritis Rheum Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-kappa B Eur J Immunol Cited by (159) Recommended articles (6) FAQs Videos

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Autoimmunity Reviews

Volume 9, Issue 8,

June 2010

, Pages 531-535


Rheumatoid arthritis is the most common inflammatory joint disease. The etiopathogenesis of this condition has been classically explained by a T cell-driven process. However, recent studies have highlighted the possible contribution of neutrophils for the early phases of RA physiopathology. These cells are phagocytic leukocytes that play crucial roles in the acute defense against pathogens while modulating the function of other immune cells and contributing to the perpetuation of an initial inflammatory response. The herein article reviews recent progresses in the understanding of the immunopathology of RA with a special emphasis on the role of neutrophils.


Rheumatoid arthritis (RA) is a chronic immune inflammatory disease characterized by synovial hyperplasia, joint destruction and extra-articular manifestations with a significant impact on both morbidity and mortality. Although the etiopathology of this condition is not fully understood, it is known that neutrophils, macrophages, synovial fibroblasts, T cells and B cells are involved in the mechanisms that drive the onset of RA. T cells, B cells and macrophages infiltrate the synovium and form discrete lymphoid aggregates, sometimes with ectopic germinal centers, while macrophage-like and fibroblast-like synoviocytes accumulate in the intima causing hyperplasia and secreting degradative enzymes. However, before these events take place, neutrophils migrate to the synovial fluid (SF) where they phagocyte immune complexes and release powerful proteases. Neutrophils, which are part of the innate immunity, are crucial for pathogenic defense. They are the first cell type to arrive at sites of inflammation, followed by monocytes [1]. In a normal inflammatory response and upon appropriate stimuli, neutrophils are able to release cytotoxic mediators, such as reactive oxygen (ROS) and nitrogen (RNS) species and proteases into the extracellular space, generating damage to the pathogen and to the host tissues. Consequently, and after elimination of the pro-inflammatory stimulus, there is an urgent need to repair the injuries and return to a state of homeostasis. This is manifested as a shift towards anti-inflammatory signals that ultimately lead to the resolution of inflammation. At this point, neutrophils must die by apoptosis and be ingested by macrophages that are involved in clearing the inflamed area. Concomitantly, anti-inflammatory signals such as macrophage-derived lipoxins stop the influx of neutrophils and activate macrophages to phagocyte dead cells, thus pushing the inflammatory response towards resolution of inflammation [2]. In RA the mechanisms of neutrophil activation, recruitment and apoptosis are altered. This review is focused on recent developments in the immunobiology of RA, specifically regarding the contribution of neutrophils for disease progression.

Section snippets

Immune mediators production

Mature neutrophils have been considered terminally differentiated cells that have a low level of de novo protein synthesis. However, neutrophils were shown to synthesize a large variety of cytokines and chemokines under inflammatory conditions. Although neutrophils produce lower amounts of these molecules than other cells, their higher number at inflammatory sites makes them an important source for these proteins. Cytokines and chemokines are crucial to amplify inflammation, by recruiting more


The traditional concept of the neutrophil as a professional phagocytic cell only able to destroy pathogens and tissues seems to be at odds with recently obtained data. Neutrophils in chronic inflammatory settings, as is the case of RA, are able to interact with other cells and to regulate their functions. They produce inflammatory mediators that contribute to the regulation of the inflammatory process and are able to adopt different phenotypes like APC or osteoclasts. In summary, neutrophils

Take-home messages

Neutrophils are the first cell type to arrive at sites of inflammation.

Under chronic inflammatory conditions neutrophils are able to release protease-rich granules and to produce high amounts of ROS.

Neutrophils secrete immune mediators which can activate themselves and other immune cells, triggering positive regulatory feedbacks which lead to acute and persistent inflammation.

Neutrophils live longer in inflammatory sites, augmenting the release of powerful destructive enzymes.

Neutrophils are


This work was supported by a fellowship from Fundação para a Ciência e a Tecnologia (FCT) SFRH/BD/40513/2007 and partially supported by a grant from Sociedade Portuguesa de Reumatologia and FCT grant PTDC/SAU-OSM/73449/2006.

(Video) Neutrophil Contribution to Inflammation and Autoimmunity in Rheumatic Disease

References (40)

  • G.S. Ashcroft et al.

    Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing

    Nat Med


    (Video) Neutrophils in Inflammation and Autoimmunity

  • A. Cross et al.

    Secretion of oncostatin M by neutrophils in rheumatoid arthritis

    Arthritis Rheum


  • J. Auer et al.

    Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis

    Arthritis Res Ther


  • T. Kasama et al.

    Expression of vascular endothelial growth factor by synovial fluid neutrophils in rheumatoid arthritis (RA)

    Clin Exp Immunol


  • G.S. Cheema et al.

    Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases

    Arthritis Rheum


  • L.K. Assi et al.

    Tumor necrosis factor alpha activates release of B lymphocyte stimulator by neutrophils infiltrating the rheumatoid joint

    Arthritis Rheum


  • E.R. Vossenaar et al.

    Citrullination of synovial proteins in murine models of rheumatoid arthritis

    Arthritis Rheum


  • J.L. Eyles et al.

    Granulocyte colony-stimulating factor and neutrophils—forgotten mediators of inflammatory disease

    Nat Clin Pract Rheumatol


  • L. Bjorkman et al.

    Phagocyte-derived reactive oxygen species as suppressors of inflammatory disease

    Arthritis Rheum


  • J. Bylund et al.

    Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-kappa B

    Eur J Immunol


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    Why are neutrophils elevated in rheumatoid arthritis? ›

    An unbalanced energy metabolism in SLE and RA neutrophils contributes to the pathology of both diseases; increased hypoxia and glycolysis in RA drives neutrophil activation and NET production, whereas decreased redox capacity increases ROS-mediated damage in SLE.

    Are neutrophils high with rheumatoid arthritis? ›

    The association between NLR and disease activity was analyzed. Results: Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and neutrophil counts were significantly higher in RA and AS patients compared to healthy controls.

    What do neutrophils do in rheumatoid arthritis? ›

    Neutrophils regulate immune and inflammatory response in RA

    Besides secreting proteases, activated neutrophils act like macrophages or dendritic cells in the regulation of adaptive immune response.

    Can high neutrophils mean arthritis? ›

    Rheumatoid arthritis. The identification of increased neutrophils in RA synovial fluid, particularly in early disease stages, supports a role for these cells in the pathogenesis of joint destruction [81–85].

    Why would neutrophils Absolute be elevated? ›

    Neutrophilia: Neutrophilia, also known as neutrophilic leukocytosis, occurs when your neutrophil count is too high, which is often the result of a bacterial infection. To combat the infection, immature neutrophils leave your bone marrow too soon and enter into your bloodstream.

    What does it mean if neutrophils are high? ›

    Having a high percentage of neutrophils in your blood is called neutrophilia. This is a sign that your body has an infection. Neutrophilia can point to a number of underlying conditions and factors, including: infection, most likely bacterial.

    Can rheumatoid arthritis cause low neutrophils? ›

    Felty's syndrome is a rare complication of RA, first described in 1924. Its features are low neutrophils (white blood cells) in the blood, infections and leg ulcers in a patient who usually has severe RA.

    Does arthritis affect neutrophils? ›

    Therefore, neutrophils participate in the pathogenesis of arthritis by promoting the inflammatory process, degradation of cartilage, and bone resorption. The modulation of neutrophil migration and functions in RA can be considered a potential target for pharmacological intervention in arthritis.

    Can rheumatoid arthritis cause a high white blood cell count? ›

    Other high white blood cell count causes may include: Excessive physical or emotional stress (such as fever, injury or surgery). Burns. Immune system disorders such as lupus or rheumatoid arthritis.

    What do neutrophils release during inflammation? ›

    Neutrophils respond to multiple signals and respond by producing several cytokines and other inflammatory factors that influence and regulate inflammation and also the immune system (Nauseef and Borregaard, 2014; Scapini and Cassatella, 2014).

    How does rheumatoid arthritis affect white blood cells? ›

    In RA, the white blood cells of the immune system move from the bloodstream into the joint tissues. Joint fluid may increase and the white cells are found in the fluid as well.

    Does autoimmune cause high neutrophils? ›

    Reduced production of cellular ROS in circulating neutrophils increases the susceptibility of autoimmune diseases and the risk of chronic inflammation, whereas elevation of ROS in SF neutrophils may directly participate in injury of joints tissues (67, 68).

    What if neutrophils are high and lymphocytes are low? ›

    The elevation can be caused by many different conditions and may be an indicator of a severe infection, an inflammatory disorder, or cancer. High levels of neutrophils may indicate a severe infection or stress on the body. Low levels of lymphocytes may also reflect severe stress and the release of stress hormones.

    What diseases cause high neutrophils? ›

    Conditions such as heart attack, a bone fracture, septic arthritis, wounds, burns, accidents, and appendicitis can also cause high neutrophil count. An increased concentration of cortisol and adrenaline hormones and the ingestion of some drugs, such as prednisone, can cause more neutrophils to enter the bloodstream.

    What causes high white blood cell count and high neutrophils? ›

    Neutrophils: Increased levels of neutrophils in their body lead to a physical state known as neutrophilic leukocytosis. This condition is a normal immune response to an event such as infection, injury, inflammation, some medications, and certain types of leukemia.

    What bacterial infections cause high neutrophils? ›

    Causes of Neutrophilia
    • Acute and chronic bacterial infection, especially pyogenic bacteria, either local or generalised, including miliary TB.
    • Some viral infections (eg, chickenpox, herpes simplex).
    • Some fungal infections.
    • Some parasitic infections (eg, hepatic amoebiasis, Pneumocystis carinii).
    Jul 6, 2007

    Is 70 percent neutrophils high? ›

    Optimal Result: 50 - 70 %.

    Can stress cause high neutrophils? ›

    With reactive neutrophilia, there is an increase in the number of neutrophils in response to infections or stress. Anxiety can cause neutrophilia, as stress hormones in your body cause a greater than normal number of these cells to be released from the bone marrow.

    How do you treat high neutrophils? ›

    Treatment to lower your neutrophil levels will depend on the cause of neutrophilia and may include the use of:
    1. antibiotic therapy.
    2. anti-inflammatory therapy.
    3. hydration therapy (IV)
    4. chemotherapy.

    Can rheumatoid arthritis cause low lymphocytes? ›

    Lymphopenia is not uncommon in several human autoimmune diseases. Reduced total lymphocyte counts are observed in rheumatoid arthritis, insulin-dependent diabetes mellitus, Crohn's disease, systemic lupus erythematosus (SLE) and primary vasculitides.

    Can rheumatoid arthritis cause high lymphocytes? ›

    Increased Lymphocyte Infiltration in Rheumatoid Arthritis Is Correlated with an Increase in LTi-like Cells in Synovial Fluid - PMC. The . gov means it's official.

    What cells are affected by rheumatoid arthritis? ›

    Among them, T cells (5) and macrophages (6) are recognized as two critical cellular components involved in RA. The essential role of T cells in the pathogenesis of RA has been validated, including studies on the infiltration of synovial T cells in inflammatory synovium of RA (7).

    Does a CBC show rheumatoid arthritis? ›

    Interpreting Results. A CBC test will show the measurements of the different blood components, but not all of them are relevant for RA. Low white blood cell counts can indicate an autoimmune condition, cancer, or bone marrow problems. High white blood cell counts can mean you have an infection or inflammation.

    What do neutrophils do in acute inflammation? ›

    The major role of the neutrophil in acute inflammation is to phagocytose microorganisms and foreign materials. Phagocytosis is seen as a three-step process in which the injurious agent undergoes recognition and neutrophil attachment, engulfment, and killing or degradation.

    Are neutrophils high with chronic inflammation? ›

    Neutrophils are normally the first responders to acute inflammation and contribute to the resolution of inflammation. However, in chronic inflammation, the role of neutrophils is less well understood and has been described as either beneficial or detrimental, causing tissue damage and enhancing the immune response.

    What is the function of neutrophils in the inflammatory response quizlet? ›

    Which is the role of neutrophils? Neutrophils are active in phagocytosis and the inflammatory process. Neutrophils are active in phagocytosis and the inflammatory process and thus play an important role for the immune system.

    Which syndrome is associated with leukopenia in a patient with rheumatoid arthritis? ›

    Felty's syndrome appears to be a variant of rheumatoid arthritis with extra-articular manifestations in which leukopenia (usually due to neutropenia) and splenomegaly occur, although not always at the same time.

    What is the blood test for rheumatoid arthritis? ›

    An anti-CCP antibody test — also called an ACCP test or CCP-test — looks for the presence of these antibodies to help confirm rheumatoid arthritis. An anti-CCP test can also help doctors determine the severity of a rheumatoid arthritis case.

    Does arthritis lower white blood count? ›

    A low white blood cell count can be an indicator of certain conditions, including lupus, rheumatoid arthritis, vitamin deficiencies, or a side effect of cancer treatment.

    What autoimmune disorders cause low neutrophils? ›

    Autoimmune diseases
    • Granulomatosis with polyangiitis (formerly called Wegener's granulomatosis)
    • Lupus.
    • Rheumatoid arthritis.

    What is the relationship between neutrophils and lymphocytes? ›

    Background. Exposure to viral or bacterial pathogens increases the number of neutrophils with a relative decrease in lymphocytes, leading to elevated neutrophil to lymphocyte ratio (NLR).

    What does high neutrophils and high lymphocytes mean? ›

    A High Neutrophil-Lymphocyte Ratio Is Associated With Increased Morbidity and Mortality in Patients With Coronavirus Disease 2019.

    What should neutrophil to lymphocyte ratio be? ›

    We have identified that the normal NLR values in an adult, non-geriatric, population in good health are between 0.78 and 3.53.

    Can inflammation cause high neutrophils? ›

    In certain organs such as liver and adipose tissue, few neutrophils are detected in normal homeostatic conditions. However, upon an inflammatory state induced by experimental obesity, neutrophil numbers increase rapidly and a metabolic imbalance is slowly generated (Talukdar et al., 2012).

    Can rheumatoid arthritis cause low neutrophils? ›

    Felty's syndrome is a rare complication of RA, first described in 1924. Its features are low neutrophils (white blood cells) in the blood, infections and leg ulcers in a patient who usually has severe RA.

    What does elevated WBC and neutrophils mean? ›

    Neutrophils are a type of white blood cell. They help you fight infection. If there are too many neutrophils in your bloodstream, you may develop leukocytosis, or a high total white blood cell count. You may have symptoms such as fevers or recurring infections. These symptoms may be signs of an underlying condition.

    Can methotrexate cause high neutrophils? ›

    Results. Neutrophil counts in the peripheral blood and BAL were significantly raised in the low MTX-exposure group compared with the high MTX-exposure group (P = 0.018 and 0.038, respectively).


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