Increased ILC3s associated with higher levels of IL‐1β aggravates inflammatory arthritis in mice lacking phagocytic NADPH oxidase

Abstract

The role of redox regulation in immune-mediated arthritis has been previously described. However, the relationship between innate immune cells, including innate lymphoid cells (ILCs) and phagocyte-derived ROS, in this process remains unclear. Here, we characterize ILCs and measure the IL-1 family cytokines along with other cytokines relevant to ILC functions and development in serum-induced arthritic joints in wild type and phagocytic NADPH oxidase (NOX2)-deficient Ncf1 −/− mice. We found more severe serum-induced joint inflammation and increased NCR + ILC3s in inflamed joints of Ncf1 −/− mice. Furthermore, in vitro stimulation with IL-1β on Tbet + ILC1s from joints facilitated their differentiation into ROR-γt + ILC3s. Moreover, treatment with IL-1 antagonists effectively lowered the proportions of NCR + ILC3s and IL-17A producing ILC3s in Ncf1 −/− arthritic mice and ameliorated the joint inflammation. These results suggest that NOX2 is an essential reg- ulator of ILC transdifferentiation and may mediate this process in a redox-dependent manner through IL-1β production in the inflammatory joint. Our findings shed important light on the role of ILCs in the initiation and progression in tissue inflammation and delineate a novel innate immune cell-mediated pathogenic mechanism through which redox regulation may determine the direction of immune responses in joints.Keywords: chronic granulomatous disease r innate lymphoid cells r NADPH oxidase r reactive oxygen species r serum-induced arthritis Additional supporting information may be found online in the Supporting Information section at the end of the article.

NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities

“…A growing body of evidence supports important regulatory roles of leukocytes-derived ROS in inflammatory arthritis ( 21 , 22 , 30 ). In our previous finding, NOX2-deficient mice developed enhanced inflammatory arthritis.…”

“…About 250 µl serum was acquired from each K/BxN mouse, and approximately 2 mL serum was collected from 5-8 K/BxN mice in one batch. Serum was mixed from different batches and 100 µl serum plus 50 µl PBS were injected into one mouse for induction on day 0 and again on day 2 ( 21 , 22 ). Clinical scores were analyzed as the sum of the four limbs, and which would be given a score of 0-3 per limb.…”

“…Co., Ltd., Tokyo, Japan). The measurements were performed before injection on day 0 and once a day after injection from day 1 to day 7 when the mice were sacrificed ( 21 , 22 ). Ankle and wrist tissues were collected for neutrophil isolation.…”

Alteraciones inflamatorias clínicas y moleculares en enfermedad granulomatosa crónica

“…En la EGC la mayor producción de IL-1b favorece la diferenciación de Tbet+ILC1s a RORγ+ILC3s, lo cual puede contribuir a la iniciación y perpetuación del perfil de inflamatorio. 39 El incremento de los linfocitos TH17 se ha encontrado ligado a la patogénesis de las enfermedades autoinmunes. Se cree que los niveles elevados de linfocitos TH17 e IL-17, IL-21 e IL-23 en EGC podrían participar en la génesis de las enfermedades autoinmunes.…”

Innate lymphoid cells in inflammatory arthritis

“…Thus, the interaction between ILCs and T cells plays an essential role in mounting the most appropriate immune responses against the threat encountered by the individual to maintain homeostasis. However, chronic exposure to environmental stimuli will shift a tissue-protective response into chronic inflammation and pathological injury, in which ILCs were dysregulated or overreacted to some extent [24]. In recent years, it has been reported that ILCs were involved in the pathogenesis of many rheumatic diseases, most of which are characterized by systemic autoimmune responses and persistent uncontrolled inflammation.…”