WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis

Biswas, Amlan; Shouval, Dror S.; Griffith, Alexandra; Goettel, Jeremy A.; Field, Michael; Kang, Yu Hui; Konnikova, Liza; Janssen, Erin; Redhu, Naresh Singh; Thrasher, Adrian J.; Chatila, Talal A.; Kuchroo, Vijay K.; Geha, Raif S.; Notarangelo, Luigi D.; Horwitz, Bruce H.; Snapper, Scott B.

doi:10.1038/s41467-018-03670-6

Cited by 41 publications

(47 citation statements)

References 54 publications

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“…Macrophages, when activated, contribute to innate immunity against these intracellular pathogens, suggesting that the overall consequences of Dock8 loss in macrophages, namely impaired migration, may be physiologically less important than the consequences of DOCK8 loss in lymphocytes or dendritic cells . Recently, loss of Dock8 in mouse bone marrow‐derived macrophages was found to impair Il‐10‐induced STAT3 signaling and suppressive effects of anti‐inflammatory M2‐type differentiated macrophages . Additional studies are needed to determine whether loss of DOCK8 in macrophages also affects other processes such as phagocytosis.…”

Section: Other Infectionsmentioning

confidence: 99%

“…Although most DIDS patients lack overt autoimmune disease, many have autoantibodies against cytoplasmic antigens and have expansion of autoreactive CD21 −/low CD10 − CD27 − phenotype B cells, indicating impaired peripheral B cell tolerance . Using culture systems of mouse cells, impaired differentiation of anti‐inflammatory M2‐type macrophages lacking Dock8, including their decreased ability to suppress T cell proliferation, was observed . However, whether this actually occurs in DIDS patients and contributes to their developing autoimmune disease is unknown.…”

Section: Autoimmunitymentioning

confidence: 99%

“…52 Recently, loss of Dock8 in mouse bone marrow-derived macrophages was found to impair Il-10-induced STAT3 signaling and suppressive effects of anti-inflammatory M2-type differentiated macrophages. 53 Additional studies are needed to determine whether loss of DOCK8 in macrophages also affects other processes such as phagocytosis.…”

Section: Virus Infec Ti On S Of the S K Inmentioning

confidence: 99%

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Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Jing

Angelus

et al. 2018

Immunological Reviews

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Summary: DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring 1) profound susceptibility to virus infections of the skin, with associated skin cancers, and 2) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.

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Section: Other Infectionsmentioning

confidence: 99%

Section: Autoimmunitymentioning

confidence: 99%

Section: Virus Infec Ti On S Of the S K Inmentioning

confidence: 99%

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Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Jing

Angelus

et al. 2018

Immunological Reviews

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“…WASp has also been shown to be important for anti‐inflammatory macrophage function. Expression of WASp in macrophages regulates the development of colitis in mice …”

Section: Human Disease Caused By Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

“…Expression of WASp in macrophages regulates the development of colitis in mice. 95 WAS is the prototypic immune dysregulatory syndrome affecting the actin cytoskeleton. Its absence or dysfunction has widespread effects on both lymphoid and myeloid cells.…”

Section: Regulators Of the Actin Cytoskeletonmentioning

confidence: 99%

Primary immunodeficiencies caused by mutations in actin regulatory proteins

Janssen

2018

Immunological Reviews

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Summary The identification of patients with monogenic gene defects have illuminated the function of different proteins in the immune system, including proteins that regulate the actin cytoskeleton. Many of these actin regulatory proteins are exclusively expressed in leukocytes and regulate the formation and branching of actin filaments. Their absence or abnormal function leads to defects in immune cell shape, cellular projections, migration, and signaling. Through the study of patients’ mutations and generation of mouse models that recapitulate the patients’ phenotypes, our laboratory and others have gained a better understanding of the role these proteins play in cell biology and the underlying pathogenesis of immunodeficiencies and immune dysregulatory syndromes.

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Evolving Experimental Platforms to Evaluate Ulcerative Colitis

et al. 2022

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tissue thus altering tissue integrity, anatomy, and physiology subsequently affecting the overall health-related quality of life (HRQoL) of afflicted individuals. [1][2][3] It is estimated that the lifetime financial loss associated with the typical UC patient can be greater than $1 million/patient to cover direct and indirect medical expenses including treatment, hospitalizations, and general medical care. [3][4][5][6][7] As an example, vedolizumab and adalimumab treatment for UC had total direct medical costs of $100 022 and $151 133, respectively, per patient. [8] This number varies greatly depending upon the severity of the disease with a greater expense attributed to those exhibiting a poor clinical disposition. At the domestic level, the total cost to treat UC is estimated to be between $4-14 billion per year which seems to rise on an annual basis. [3,6,7] The specific etiological basis regarding the initiation and progression of UC is currently unknown. Physical manifestations of severe UC take the form of ulcerations affecting the mucosal lining, specifically along the length of the affected large intestine and rectum as depicted in Figure 1. These lesions contain an overabundant accumulation of innate and adaptive immune cells, including T cells, that promote an inflammatory environment Ulcerative colitis (UC) is a multifactorial disease defined by chronic intestinal inflammation with idiopathic origins. It has a predilection to affect the mucosal lining of the large intestines and rectum. Management of UC depends upon numerous factors that include disease pathogenesis and severity that are maintained via medical or surgical means. Chronic inflammation that is left untreated or managed poorly from a clinical stance can result in intestinal ulceration accompanied by resulting physiological dysfunction. End-stage UC is mediated by surgical intervention with the resection of diseased tissue. This can lead to numerous health-related quality of life issues but is considered a curative approach. Regimens to treat UC are ever evolving and find their basis within various platforms to evaluate and treat UC. Numerous modeling systems have been examined to delineate potential mechanisms of action. However, UC is a heterogenous disease spanning unknown genetic origins coupled with environmental factors that can influence disease outcomes and related treatment procedures. Unfortunately, there is no one-size-fits-all model to fully assess all facets of UC. Within the context of this review article, the utility of various approaches that have been employed to gain insight into different aspects of UC will be investigated.

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WASP-mediated regulation of anti-inflammatory macrophages is IL-10 dependent and is critical for intestinal homeostasis

Cited by 41 publications

References 54 publications

Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Insights into immunity from clinical and basic science studies of DOCK8 immunodeficiency syndrome

Primary immunodeficiencies caused by mutations in actin regulatory proteins

Evolving Experimental Platforms to Evaluate Ulcerative Colitis

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